The hardest part of the game are the Clickers. They take two headshots to kill and have generally higher health and while they're blind, they have REALLY sensitive hearing (to the point where even full speed sneaking is audible at a certain distance, so you have to move at about half of your usual "slow" speed to avoid getting caught). They can only be stealth killed if you have a shiv (which is a disposable tool that lasts only two uses after you upgraded it and spends much of the game as a one-use item.....or the entire game if you didn't find the upgrade manual) and until you learn the proper skill AND have a shiv handy it's an unavoidable one-hit kill if they make contact. And they almost always come in groups, and if not they're surrounded by regular Infected that still have their eyesight and just bum rush you. If you lose stealth even once, you usually get rushed and killed as soon as a single Clicker touches you because you're distracted by too many enemies.
Speaking of enemies, the humans in this game are fucking SMART. They can flank, and Joel has so little health even when upgraded that it's often a death sentence if a guy with a gun gets around you. And they'll gladly throw Molotovs at you when you're hiding. Not to mention that you can't block with the fighting system, so any mistimed or misaimed hit means you'll likely take a few whacks. And bad guys all attack you at once, so fighting more than one person in melee is a death sentence and guys with guns will shoot you with impunity if you get caught up in a brawl.
Making it through an encounter takes a ton of intelligence and cleverness. You usually need to distract and isolate enemies to take them out through stealth, and every shot you make should be the most damaging one possible from your position. The best option is usually to just never let the enemies know you're even there in the first place.
