The story takes place in Spain, and the Spanish spoken by the villagers in the game is called Castilian. (Which has a different pronunciation than the form of Spanish, known as Español, commonly spoken by many Latino.) The currency used throughout the game is the Peseta, which some may find curious, as Spain had switched to Euros in 2002, and the game takes place in 2004. But this may have been done to show how behind the times the area is compared to the rest of Spain, due to it's remoteness and due to it's inhabitants being afflicted with the "Plago" parasite, transforming them into, essentially, "zombies". As such, it would make perfect sense for them to still have the older currency in their pockets, etc. Especially if they've all been in their, "zombie-like" state for, at least, two years.
This is the first Resident Evil game where Umbrella isn't responsible for the monsters and bio organic weapons (BOW) creations. Umbrella is gone by this point, and may yet come back.
The Matilda handgun was named after the character with the same name from the movie Léon: The Professional (1994), which also had a main character called Leon.
Resident Evil 4 was in production for many years due to the constant changes it went through. The game was scrapped and started again four times. The first scrapped version would have featured a character called Tony Redgrave, the son of Ozwell Spencer mentioned in Resident Evil (1996) and Resident Evil (2002), who gets superpowers from being infected with the G-virus. However, producer Shinji Mikami felt that the concept strayed too far from the series' survival horror roots. This version eventually became its own game (and franchise), titled Devil May Cry (2001), with Tony changed to Dante.
This Resident Evil used all new enemies that were not in any of the previous games. No zombies, no Cerberus, no crows, no giant spiders, no tyrants, no hunters, no lickers made it to this installment.