Barrera vs Pacquiao I

On November 16, 2003, Barrera was defeated by Filipino boxer Manny Pacquiao in the eleventh round when Barrera's corner threw in the towel, earning Pacquiao his third world championship in third weight division (Barrera was the recognized lineal champion and his Ring Magazine title was also on the line when he fought Pacquiao).

On June 19, 2004, Barrera defeated former WBA bantamweight title holder Paulie Ayala in Los Angeles by a tenth-round knockout.

Super featherweight

Barrera vs Morales III

On November 27, 2004, Barrera fought Morales for the third time and became a three division world champion by defeating Morales in a majority decision to capture the WBC super featherweight title.

On April 9, 2005, Barrera retained the title with a second round knockout against future champion Mzonke Fana in El Paso, Texas, this win also marked Barrera's 60th career win.

Barrera vs Juarez

On May 20, 2006, Barrera defended his title against American boxer Rocky Juarez with what was announced immediately after the fight as a twelve-round draw, which the judges scored 115-113, 113-115 and 114-114. However, tabulation errors were found in the judges' scorecards, leading to a final score of 115-114, 114-115 and 115-114, a split decision in favor of Barrera. He fought Juarez in a rematch bout on September 16, this time Barrera won by a unanimous decision with scores of (117-111, 115-113, 115-113).

Barrera vs Pacquiao II

Barrera fought Pacquiao in a rematch bout for the WBC International super featherweight title on October 6, 2007 in Las Vegas. Barrera was defeated by a unanimous decision with scores of 118-109, 118-109, 115-112. After the match, Barrera expressed his desire to retire from boxing, however no official confirmation had been given. On February 13, 2008, Barrera announced to the media that he would fight the winner of the Marquez vs Pacquiao bout on March 15. The winner of this turned out to be Pacquiao, in a highly disputed split decision. However, Pacquiao's move to the lightweight division and subsequent capture of the WBC lightweight title ensured that a third fight between the two would not happen.