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.
Was the first Resident Evil to be presented in high definition.
This is the first Resident Evil game where you can use a GPS map during game-play. The revalations series later added a gps/mini map similar to 5.
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 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.