The Bills drafted Losman, a quarterback who played collegiately at Tulane, in 2004 with the 22nd pick in the first round of the NFL Draft. As of late 2004, he had made brief appearances in three games, completing three of five passes for 32 yards and one interception while backing up Drew Bledsoe.

Losman grew up in Venice, California, the son of an American father and Mexican mother and played quarterback at Venice High School. Losman's parents divorced when he was 5. His mother juggled a full time job as a customer service representative and a part time job as an usher at the Great Western Forum. He attended college at UCLA and transferred to Tulane.

In 2002, in his first year as a full-time starter, Losman led the Green Wave to an 8-5 record and a victory in the inaugural Hawaii Bowl.

Losman finished his college career having completed 570 of 987 passes (57.7 percent) for 6,754 yards, 60 touchdowns and only 27 interceptions. He also ran for 241 yards with 10 scores on 237 carries.

Following the Buffalo Bills' February 2005 release of Drew Bledsoe, Losman was named the team's starting quarterback by head coach Mike Mularkey.

In the first game of the 2005 season (Losman's first professional start) Losman led the Bills to a 22-7 victory over the Houston Texans. Losman was unable to repeat this performance in following weeks - guiding the Bills to three consecutive losses. This below average performance caused the Bills to bench Losman in favor of veteran quarterback Kelly Holcomb. After a 1st quarter Holcomb head injury during Week 10, Losman saw playing time and led the Bills to a 14-3 victory over the Kansas City Chiefs. Since then, the Bills went on to lose all but one of their remaining games of the 2005 season.