The game starts out in a pub, in London, England. After some words with Talbot, who is interested in purchasing Nathan's ring, a brawl starts out. Not long after, they meet up with Talbot's client, Katharine Marlowe, who steals Nathan's ring and gets away. Talbot's henchman, Charlie Cutter, shoots both Nathan and Sully and leaves them for dead.
The game cuts to a flashback, back to when Drake was a child, in Cartagena, Colombia. He is trying to find Sir Francis' ring, and eventually runs into Sully, who he doesn't know yet. Nathan eventually steals a key from Sully, returns to the museum and steals the ring, but not before getting caught by Marlowe. He manages to escape, with the help of Sully, and thus begins the relationship between Nathan Drake and Victor "Sully" Sullivan.
The games cuts back to the present, where we see Nathan and Sully alive and kicking; they are friends with Cutter, and they set up this encounter with Talbot and Marlowe. They track down Marlowe and eventually retrieve Lawrence of Arabia's notebook, where they see he was commissioned to try and track down the Iram of the Pillars (the Atlantis of the Sands). This leads them on a long and perilous journey, through rough waters and the Rub' al Khali desert.