Melee weapons can only be used a few times before they break down. Ammo is very limited and initially, the reloading speed and firing rate are slow. There is a selection of close and long-ranged guns, along with melee weapons that can be modded, regular fist fighting, and items such as Molotov cocktails, smoke bombs, and nail bombs.

Enemies include various five types of infected (Runners, Stalkers, Clickers, Bloaters, and Spore Cadavers) each with their own characteristics, but also humans from the military groups and other survivors. Similarly, the survival horror theme with limited ammo and health makes him very vulnerable to attacks and a stealth approach is often more effective. Joel is however not as strong or acrobatic and he often needs to use ladders, planks, and other items to climb and get around. Similar to the developer's previous Uncharted games, gameplay combines action elements, exploration, and puzzle-solving. Ellie can also be controlled by herself for some extensive parts in the later chapters. The player controls Joel from a third-person perspective. After some events and revelations about Ellie's importance, Joel and Ellie end up together and their journey is documented in the course of a year and a few months, spread over five seasons. During a mission, they get into contact with a Fireflies member who offers stolen weapons back if they escort the 14-year-old girl Ellie out of the city. Together with his friend Tess, he survives by smuggling goods in and out of the city. Others are part of the resistance group the Fireflies, while Joel is a member of an independent group. Independent groups of survivors have organized themselves into military outfits that quarantine zones, hold curfew, and distribute rations. Twenty years later, civilization is almost entirely destroyed. The opening sequence is set during the outbreak and it has Joel escape the invaded city with the help of his brother Tommy. The game starts in a contemporary, but post-apocalyptic version of Boston twenty years after the outbreak of the Cordyceps Brain Infection (CBI), an infection spread by a mushroom that turns anyone infected into zombie-like creatures in two days. The story focuses on the two characters Joel and Ellie. The Last of Us is a survival horror action game.

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