This is the first Resident Evil game where all previous games are referenced, in so much as upon completing the game, a history of Resident Evil is unlocked detailing the past 70 years. This means that it is finally explicitly confirmed that the survivors of Resident Evil (1996)/Resident Evil (2002) were Chris, Jill, Barry, Brad and Rebecca, and that the level "Umbrella's End" from Resident Evil: The Umbrella Chronicles (2007) is officially considered canon.

This is the first main Resident Evil game where the subtitles are enabled during cut-scenes. All the previous games had none or a very limited amount of subtitles.

In "Lost In Nightmare" scenario, if you attempt to leave the mansion through the front door, you will be able to play the game using the camera angle style of the earlier Resident Evil games when the camera didn't move, but was fixed camera angles.

The first Resident Evil game to be presented in high definition.

This is the first Resident Evil game that has the swear word "fuck" in it, but its only used twice. One for the main game and one for the downloadable scenario "Desperate Escape". It is used strikingly when the BSAA pilots (including Doug in the DLC scenario, "Desperate Escape") are being caught by the flock of Kipepeo.

This is the first Resident Evil game where you can use a GPS map during game-play.

When playing as Sheva, the character is displayed on the right side of the screen, as opposed to Chris who is always on the left side. This is because Sheva is left-handed, and Chris is right-handed.

The beginning of the mansion of the "Lost In Nightmare" scenario bears a striking resemblance to the mansion of Resident Evil Remake. Some resemblances include the main hallway's staircase, the rear staircase, the dining room, the stairway hallway that had a birdcage in the Remake game, the piano song "Moonlight Sonata" to be able to take an emblem, and to use that emblem to open a door, and a monster crashing through windows.

On February 10, 2010, Capcom released a "Lost In Nightmare" mini-game for download. This scenario covers the events of the flashback Chris told to Sheva when they were boating on a fan-boat in the marshlands. And on March 4th, 2010, another scenario, "Desperate Escape" was released that is based on Jill Valentine and Josh Stone making their escape from the industrial complex after Jill is restored to her normal self.

Of the Umbrella B.O.Ws the Licker is the only one to make a return.

Like the other playable characters in the game, Albert Wesker can also perform physical attacks on stunned enemies. One of these attacks is called "Tiger Uppercut"; a reference to a special move by Sagat from the Street Fighter series, a game also developed and published by Capcom.

This is the only Resident Evil game until Revelations 2 where a Resident Evil history fact is used while loading up the next scenes.

It's revealed in the game that the Progenitor Virus that Umbrella researched in the past was created by a flower species.

The music heard in chapter 1-1 and 1-2 is the same music as heard in Resident Evil (2002) when walking around the first floor of the residency area.

A merchant similar to the one from Resident Evil 4 (2005) was supposed to appear in the game which was suppose to be the man who gives Chris and Sheva their weapons in chapter 1-1 (Reynard Fishter), but he was replaced by a simple weapons upgrade screen in between missions.

Umbrella has been out of business at this point, but in the underground when Chris dusts off something, it has Umbrella's logo on it, because this is an old Umbrella laboratory taken over by Tricell.

This is the first Resident Evil main series where if the player character switches equipped weapons, they can be seen physically swapping weapons instead of going into a menu to change a weapon and exit the menu with a newly equipped weapon. Plus, it's the first of the main series where the opening of the inventory menu runs in real time. This means that if the player opens the inventory menu, the game's action and time will not pause, and that enemies can keep approaching the players and can attack at any time.

The prison basement area of the mansion from "Lost In Nightmare" scenario resembles the prison of the island base from Resident Evil 4 (2005) before the end of that game.

Sheva's shoulder tattoo means 'hero' in Swahili.

The pathogen responsible for the deaths and mutations of the locals in this game is the Type 2 Plagas, while three people were killed by Uroboros. The Type 1 Las Plagas was seen in Resident Evil 4 (2005). The biggest differences with the Type 2 is that Type 1 needs to be inhaled or injected and requires time to incubate, is extremely intolerant to sunlight, and that the infected hosts can be controlled by higher Plagas; Type 2 Plagas have been engineered for oral insertion which removes most of the incubation time, are fully resistant to sunlight, and are much more autonomic.

The returning enemies of Resident Evil 4 (2005)'s new line of enemies are: chainsaw users, Gatling Gun users and a giant creature.

Jill Valentine's likeness was taken from the character Fiona Belli in Haunting Ground (2005) which is one of Capcom's game from the past as they both share the same face and hairstyle.

This game was the first Resident Evil to be released on the PlayStation 3 and Xbox 360.

Resident Evil 5 is the first main entry in the series to be produced after series' creator Shinji Mikami had left the franchise. Before the game was released, he claimed that he wasn't going to play the game, predicting that he wouldn't like it anyway since he hadn't made it himself. When he finally got around to play it, he commended Capcom's hard work, but stated that he wasn't especially happy or sad about it; he simply didn't like the idea of a Resident Evil game that was different to his style.

In Chris's flashback he explains to Sheva, a scene showing both Jill and Chris doing battle against Wesker. In "Lost In Nightmare" scenario, you as the player fight that battle against Wesker.

Actress Eva La Dare once acted in a short film called Evil Resident (2002) as a character called Eman Valentine. Although the film is completely unrelated to the Resident Evil games, years later she was hired for the role of Sheva Alomar in this game, which coincidentally has a character named Jill Valentine.

During the game a poster advertising an album by Paula Hopkins, entitled "Mother", can be seen on various walls in chapter 1-2. This exact same poster can be seen in a previous Capcom game; Dead Rising.

Wesker voice actor D.C. Douglas also performed facial capture during his recording sessions.

First Resident Evil game presented in Dolby TrueHD 5.1 surround sound.

The "Lost in Nightmare" scenario has the fewest enemies in the game, and the fewest type of enemies. There's only two types of enemies, one of which includes the classic zombies that play dead on the floor and may jump up and grabs you.

By installing the "Lost In Nightmare" scenario, the file also comes with a new version of the mini-game Mercenaries, then called "Mercenary Reunion" where both Barry Burton and Rebecca Chambers, last seen in Resident Evil 1 make a reappearance.

Although he is the cause of many of the events in the entire Resident Evil series, Oswell E. Spencer, the man who founded the Umbrella Corporation, is almost never seen. He makes his only officially credited appearance in this game, where he also meets his doom, by Wesker. It has been suspected that Spencer made a brief appearance in Resident Evil: The Umbrella Chronicles (2007) as an unidentified Umbrella official fleeing the destruction of Raccoon City in a helicopter. Although this man's appearance (half-long gray hair, nasal tube) seems to resemble Spencer, it is revealed by Spencer's notebook in Resident Evil 5 that he was actually nowhere near Raccoon City during its destruction.

Tricell is the company responsible for the biohazard in Africa, after taking control of various Umbrella projects in the area.

In Chapter 6-2, if you look through one of the monitors, and zoom in using a rifle scope, you can clearly see the FOX News Channel logo displayed.

During the DLC mission Lost in Nightmare a file can be found referring to the 13 original Wesker-children in project W. Albert Wesker Alex Wesker Derek Wesker Felicia Wesker Hans Wesker (deceased) Hiro Wesker Irma Wesker Jonah Wesker Ken Wesker Laura Wesker Marco Wesker Miles Wesker William Wesker.

This is the first Resident Evil game where you earn PlayStation 3 trophies and Xbox points for accomplishments.

The large monsters that appear in the "Lost In Nightmare" scenario bear a resemblance to the mutated version of Steve Burnside from Resident Evil - Code: Veronica (2000). They also fight similarly to Steve and the Executioner Majini by swinging an axe. In Code: Veronica, Wesker claimed to have taken Steve's corpse to harvest the T-Veronica virus. The appearance of the monsters in the "Lost in Nightmares" might suggest that they have done further experimentation on the virus.

This is the second Resident Evil where Jill Valentine was on the side of Wesker (first time was in the first Resident Evil game, but not knowingly he's evil), and her first time where she followed his evil ways, although under the influence of the Progenitor 30 chemical, which is supplied by a device on her chest. This device was originally supposed to be on her head, but this was changed to her chest, which the developers admitted would be 'more sexy'. This plot element would later be used in the movie adaptations Resident Evil: Afterlife and Resident Evil: Retribution of the game series.

Returning characters from previous Resident Evil games are: Chris Redfield, Jill Valentine, and Albert Wesker. Barry Burton and Rebecca Chambers make an appearance in the 'Mercenary Reunion' mini-game, but not in the main game. Barry Burton was briefly considered to appear in the main game as well, but he later became a main character in Resident Evil: Revelations 2 (2015) which chronologically takes place after this game.

This is the first time that Jill Valentine is seen as a blond with a different hair style, instead of a brunette with her hair down to the sides. The same change in appearance was carried over into the movie adaptations Resident Evil: Afterlife bonus scene after the beginning of the end credits, and Resident Evil: Retribution, of the series.

Original artwork showed that as Jill dragged Wesker out of the castle window to her death in the flashback, she would stab him in the eye. Wesker would therefore later resurface with a bionic eye. He was also supposed to be able to control Uroboros with his mind.

As evidenced by the trailer, the game was originally supposed to be a single player experience like Resident Evil 4 (2005), and remove the Plagas introduced in RE4 in favor of bringing back the T-virus and classic zombies from Resident Evil (2002), but much faster-moving). The Umbrella corporation was also set to make a complete return, judging by a planned scene where Chris Redfield falls into a chasm and ends up in an Umbrella waste management facility below.

Several smaller Uroboros creatures and a Tyrant monster were originally slated to appear, but the game's developers decided that Wesker with superpowers and one giant Uroboros monster were sufficient already.

The game went through many changes in story and characters. Chris Redfield was much less muscular in early versions than in the finished game. Barry Burton from Resident Evil (2002) as well as several BSAA team members were meant to appear as supportive characters who would provide backup to Chris at certain moments; Sheva was originally just a non-playable member of a local militia. This was changed to make Sheva partner up with Chris, and a playable character in the two-player mode. Jill's death was originally supposed to happen only in one possible storyline in the game, where she was to be found again later, imprisoned in a capsule by Tricell and rescued by Chris; in a different scenario, she wouldn't die, but team up with Barry early on. In the finished game, there is only a single storyline where Jill is presumed dead, but makes a surprise return, brainwashed by Wesker.

Although this is not the first game in the series to feature Albert Wesker as an adversary, it is the first game where he is part of a boss fight.

During development, director Toshio Ohashi, noted the team used the film "Black Hawk Down" as inspiration when designing the villages found early on in the game.

The "Eye of the Tiger" trophy is a shout out to the famous song of the same name by the band Survivor. Appropriately, the trophy is earned Survivors Mode.

Mistakes

In the beginning of the game, when the African Soldier stops Chris and Sheva to check for their papers, he has his AK out but, in the next scene, it is on his back a second later.

In Chapter 4-1, as a tunnel is collapsing all around and both play characters are running, they make a dive for the descending door twice.

The Gatling Gun is incorrect in this game, in real life, the Gatling Gun is a hand crack gun that it attached to a turret of some kind. In the game, it's a Mini Gun that runs off a battery.

Some weapons start out with much less ammunition than they would usually have. The Beretta 92FS pistol, for example, can carry 15 rounds, but can only carry 10 in-game.

When Chris and Sheva need to break down the door only to find DeChant and Alpha Team dead, it shows both Chris and Sheva breaking the door down, but in the cut scene only Chris is breaking down the door with Sheva right behind him.

If a player character fires a weapon in the cutscenes, the ammunition level stays the same.

Chapter 2:1 Storage Facility, after the first encounter with the Kipepeo flying parasites the water in the tunnel behind the locked door is flowing up the slope towards you instead of downwards.

An RPG-7 is shown being fired from a helicopter. Since the RPG-7 produces considerable backblast, it would be extremely perilous to fire one from a helicopter.

During the cut-scene at the beginning of Chapter 4-1, the BSAA patch on Chris' shoulder does correctly say BSAA, but the full name and North America are spelled out in reverse, e.g. aciremA htroN.

Spelling and grammar errors in subtitles.

Non-human enemies can drop items, even though there is no reason for them to carry them.

When Chris and Sheva reach the part of the cave with the flowers, Chris states that no one has been there for a while. The powered-on electric lights would suggest to the contrary.

Chris and Sheva were never given the orders to retreat, what actually happen is that they decided to flee but changed there mind once Chris decided to locate Jill. Yet, all the characters act as if they got those orders to do it. This means that either Capcom overlooked this mistake or cut out a section of the game that explains this.

Sheva calls Wesker's ship a tanker. It is, in fact, a cargo ship.

During the fight against Jill, Sheva says 'Now! Hold her down!' when you are actually supposed to shoot the device on her chest.