Leon knows Spanish. All the letters that are left around are in Spanish, but we as the players simply see Leon translating it in his head. That's why all the Ganado leave letters all around: they assume he's American and won't be able to read them. If you think about it, he is quick to say "Hasta luego" when he thinks he's going to kill Mendez, which suggests that he does know Spanish. The government would hardly send in an agent who had no idea of the local language.
That also explains why Mendez, Saddler, and everyone else bothers to speak to Leon in a heavily accented English: they thought he wouldn't understand if they spoke Spanish. As for Luis, he knew about the plan to kidnap Ashley, and when he met Leon, he just put two and two together ("Americano, si?") and concluded that he was the US agent sent to rescue her. Or probably was just used to speaking with Ada... wait, and what about the two policemen that accompany Leon at the beginning?
No problem really, the Spanish police send two English-speaking officers to make things easier for him, a sensible thing to do. Leon may be able to read Spanish perfectly well, but, regarding his pronunciation of "Luis" or "Hasta luego", he still needs to polish his pronunciation. The officers either wanted to practice their own English or did not expect a "pretty boy" like Leon to be able to know the language.
No police force is going to let a foreign agent, official or not, act in their territory without oversight.
In Darkside Chronicles, it is revealed that Leonīs mission with Krauser was in South America. This gives more credence to Leon having working knowledge in Spanish.
All the Ganados have red eyes because of the effects of Las Plagas, except for Bitores, who only has one red eye. It turns out one eye didn't turn because it's a glass eye. In a turn of Fridge Logic, however, when you pick up the glass eye, it's red.
If you have noticed throughout the game, none of the other people infected with the dominant-strain Plaga have red eyes (Saddler, Salazar, and Krauser). In Saddler's and Salazar's case, the irises have mutated into a different color (Saddler's are white and Salazar's are yellow) and Krauser maintained his blue eyes from before his infection. It could be the same thing with Mendez. Although, if it indeed was the blue eye that didn't turn and was meant to be the glass eye, it was probably a programming mistake.
When Leon firsts encounters Ada, he manages to subdue her by using his knife against her handgun and remarks:
Leon: Bit of advice: try using knives next time. Works better for close encounters.
Although good advice for the player in general, this is likely a hint for a very late part in the game where you fight Krauser: he shoots you with a TMP from afar, but when he is close to you, starts using his knife and dodging your bullets. The best way to fight him in this close encounter situation is to use the knife.
Ada eventually applies the advice when a possessed Leon starts choking her; rather than shoot Leon and risk killing him, she sticks him in the leg with a stiletto she'd been packing.
Regenerator's strained, rapid breath? Hyperventilation. Its Hyperactive Metabolism requires massive amounts of oxygen. This also explains why they try to eat Leon: they need energy. Hell, they may even be sapient, but very, very hungry.
This could be tied with them bursting when killed. Their blood pressure is massive as well to transport such quantities of oxygen.
This very well may also just be why you never find Regenerators and Iron Maidens around other enemies; given that they seem to have lost sapience, it's entirely possible that they're quite prone to cannibalism to fuel that metabolism and thus are as much of a danger to the Ganados as they are to Leon. This would also explain why you find multiple Iron Maidens in the trash disposal, as it's entirely reasonable to assume that they became more trouble than they're worth because of this.
The currency you find in the game is pesetas, which was Spain's currency up until 2001, where it switched to euros (the game takes place in 2004). However, it's highly probable that Pueblo and the surrounding areas have had no contact with outside civilization in many years by the time the game starts, explaining why you don't find any euros lying around.
Up until the Del Lago fight, you go through Pueblo in the daytime, and none of the villagers ever sprout a Plaga head. Afterwards, things always take place in areas devoid of daylight, and Plaga heads are stupidly abundant. The end-game also reveals that the Plagas are only vulnerable to a certain type of radiation...all of this adds up to a simple conclusion: Las Plagas are lethally vulnerable to UV radiation. The Fridge Brilliance behind this is that it explains why a Plaga-headed enemy can be instantly killed with a Flash Grenade.
Leon's sudden flirtation with Hunnigan at the end seemed a bit out-of-character, considering the most blatant he got with Ada was a few admiring stares. Then remember that Ashley had just made a pass at him and is still sitting behind him, listening to every word. Sounds like Leon was trying to deflect Ashley's affection.
Saddler demanding a ransom from the president has an obvious secondary purpose besides him simply wanting money for his "religious community." If he'd just kidnapped Ashley, then returned her a few weeks later, completely out of the blue, people would start to wonder why. But if he demands money from The President in exchange for her, then when he gets paid, he can return her and it will seem like a perfectly natural course of action. The ransom demand was cover so no one would ask questions when Ashley was sent back to the US.
When people think of the word "zombie", they usually think "undead creatures that feasts on the flesh of the living". The most common complaint is that 4 doesn't have flesh-eating zombies, but rather parasite-infected people. The term itself is Older Than They Think because another usage of the word (indeed, the original usage) is that zombies are slaves with no free will of their own. Thus, making the entire townspeople and the Los Illuminadoes "zombie slaves" to Saddler.
Leon gains the ability to suplex starting at the Castle, although he can never suplex a villager-type Ganado. Note that Leon's usual back kick failed in the cutscene vs Chief Mendez, leading to his capture. After being freed by the wounded axe Ganado, he gave the poor thing a partial suplex. Presumably Leon spent the rest of the journey to the Castle working out how to consistently perform a suplex. He perfected it just in time for the tougher enemies in the game.
Except that you will run into villager ganados after that and then meet the significantly tougher mercenary ganandos later on, and he won't suplex them either.
Compared to other games, the humble knife gets a massive increase in usefulness against the various enemies you encounter. Then you realize that up until 4, most of the mooks you encounter are shambling corpses and unlikely to be concerned with even fatal wounds to anything other than their head. The villagers, zealots, and soldiers, on the other hand are all living humans and vulnerable to traumatic injury, like the kind committed with a knife.
Parallel to this. Leon has become quite skilled in the use of the knife. So much that he does not even have to equip it as a separate item or put it in his inventory and he can start slashing just as quickly as he stops shooting. Adding the two points (enemies that react to pain and Leon having more skill with the knife), explains said massive increase in usefulness.
Perhaps a throwback to the earlier games, but look at Krauser when you defeat him as Leon. No blood puddle. Then who shows up to fight Ada in her scenario? Krauser. And what happens when Ada defeats him? Blood puddle. In the first few games, zombies and other creatures weren't dead until there was a blood puddle, so this may explain why Krauser wasn't dead. There was no puddle.