The first game starts when 47 escapes from a sanitarium where he has seemingly been imprisoned, being guided by a mysterious overseer. After a year, he is shown to be working for the covert International Contract Agency, or ICA, under his handler Diana Burnwood. He is sent on a mission to eliminate four crime bosses across the world, before being hired to kill a fifth target, Doctor Kovacs, at the sanitarium where 47 was imprisoned. As events transpire, 47 finds out that all his targets were part of an advanced cloning experiment, with him as the result; the perfect assassin. Professor Ort-Meyer, himself the scientific head of the experiments, is revealed to be the client who ordered the hits and, to protect himself, sends a squad of docile, highly trained 48 clones against 47. With help from a fellow agent, 47 defeats the clones and kills Ort-Meyer. In the aftermath of this revelation, 47 tries to leave his assassin past behind (in Hitman 2: Silent Assassin), seeking peace in a Sicilian monastery, but is forced to become an assassin when his mentor and friend, Father Vittorio, is kidnapped. Getting back in contact with the ICA, he arranges with Diana that he will work for them if they help trace Father Vittorio. Eventually, it is revealed that Father Vittorio's kidnapping was orchestrated by Sergei Zavorotko, the brother of one of the men whose DNA helped create 47, to bring 47 out of retirement and kill everyone who was in on a deal by Zavorotko to purchase a nuclear warhead. 47 successfully infiltrates Father Vittorio's monastery, killing Zavorotko and all his men. Though Father Vittorio begs 47 to lead a good life, the assassin decides to return to the ICA full-time.
A few years later, by the time of Hitman: Blood Money, 47's reputation has spread far and wide, with a large list of clients requesting his services. During the course of the game, it becomes clear that the ICA is under attack from a rival agency called the Franchise, who are planting incriminating evidence against 47 through one of their agents, Alexander Leland Cayne. Eventually, the agency is depleted to the point that Diana and 47 are the only ones left. 47 himself is nearly killed in Paris, prompting flashbacks over previous missions. Eventually, 47 kills one of the two Franchise assassins and is given a final contract by Diana, who has dissolved the ICA, to take down the Franchise. Soon, an old acquaintance of 47, former CIA agent Smith, reveals that the Franchise, planning to assassinate the US president, is merely a puppet organization for Alpha Xerox, a shadowy political organization who wish to monopolize the cloning techniques that gave birth to 47: they wish to kill the President before he can put a halt to their plans. 47 prevents the assassination, but must go into hiding from the Franchise and the police. At his hideout, he is seemingly betrayed and poisoned by Diana, with the Franchise preparing to cremate the assassin so his DNA cannot be used for further cloning experiments. 47's 'death' is later revealed to be a tactic which would bring 47 within killing range of everyone at the funeral, including Franchise agent Cayne. 47, his identity now a secret, goes into hiding and Diana uses the remains of the Franchise to revive the ICA.
Years later, in Hitman: Absolution, Diana seemingly betrays the ICA, exposing it to the public. When the Agency learns of her betrayal, they send operatives to eliminate her. During a mission, Diana is forced to suddenly abandon 47 when she sees that the Agency operatives are coming for her. Due to her sudden disconnection from him, 47 is nearly killed during the mission and decides to cut contact with the ICA. The Agency is eventually able to locate 47 once again. Benjamin Travis, who is Diana's superior within the Agency, contracts him to kill Diana and bring a girl she has in her care, Victoria, to the Agency. 47 infiltrates Diana's base and shoots her, but promises to keep Victoria safe from the ICA.