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The game begins with the introduction of Joel, a single father who, along with his daughter Sarah, lives in the neighborhood of Austin, Texas. On the evening of his birthday, a sudden cordyceps-like infection erupts in America that changes the people in rabid, monstrous killers. As Joel with Sarah and his brother Tommy flees for the initial chaos, Sarah gets shot by a soldier and dies in the arms of Joel.

In the twenty years that follow, the great part of civilization is destroyed or contaminated by the infection, the people who live in the heavily guarded quarantine zones. Joel now lives in a quarantine zone in Boston. By the loss of Sarah and the misery of the outbreak, Joel of a loving father and brother has turned into a ruthless smuggler. He collaborates with a woman named Tess together to get drugs, weapons, drugs and other illegal stuff into the quarantine zone. Joel and Tess Hunt a fellow smuggler named Robert because he wanted to kill Tess. After they have turned off his men they ask him and he tells him that he sold the weapons he was guilty to a resistance group called the Fireflies and they could not pay them. From frustration Tess kills him.

The Last of Us is based on the third perspective. The player will have control of Joel, while Ellie is controlled by artificial Intelligence (AI). The game includes both shooting fights and Melange, where the player must record against the infected-once people and survivors, people who have escaped the plague.

For the development of the game, Naughty Dog has developed a new AI system called "Balance of Power", where enemies react realistically in combat situations. In this way, a number of different ways are responded to seeing a weapon in the player's hands. In the case of a pistol the AI will seek coverage and enlist the help of teammates, at an iron rod it can arrive on a fist fight.