Mosley would make two more defenses of his title at lightweight, stopping both Golden Johnson and John Brown, before relinquishing his titles and moving up twelve pounds in weight to welterweight. Sugar Shane Mosley record is scoring two consecutive knockouts, setting up a huge fight against Oscar de la Hoya for the WBC welterweight title.
De La Hoya vs Mosley
Main article: Oscar De La Hoya vs. Shane Mosley
On June 17, 2000, Mosley met De La Hoya in Los Angeles for the WBC & vacant Lineal welterweight titles. After twelve rounds, Mosley emerged with a split decision victory. During the fight, neither man was in danger of going down, but both had badly swollen faces at the end and De La Hoya was bleeding from the nose for several rounds. Mosley earned a minimum of $15 million, while De La Hoya was guaranteed $35 million.
On February 8, 2003, Mosley's bout with former IBF light-middleweight title holder Raúl Márquez ended in a no contest when Mosley accidentally head butted Marquez twice in round three, which caused two very bad cuts above the eyes of Marquez.
De La Hoya vs Mosley II
Main article: Oscar De La Hoya vs. Shane Mosley II
Mosley and De La Hoya faced each other for the second time on September 13, this time with De La Hoya's Lineal/The Ring/WBC/WBA light-middleweight championships on the line. Mosley defeated De La Hoya by a controversial 12 round unanimous decision and joined the exclusive group of world boxing champions that have reigned in three or more divisions. Many fans had Oscar easily beating Mosley in this rematch but judges scored it differently regardless of De La Hoya landing over 100 more punches. Mosley testified in 2003 that he injected himself with the notorious doping agent EPO as he prepared for his light-middleweight title fight against Oscar De La Hoya, according to grand jury transcripts and doping calendars.
Return to welterweight
Margarito vs Mosley
Prior to one of the biggest fights of his career, Mosley began training with Naazim Richardson. Mosley regained the WBA(Super) welterweight title from Antonio Margarito on January 24, 2009 at the Staples Center in Los Angeles. Mosley, now 37 years old, came into the fight as a 4–1 underdog with the bookies after Margarito had spectacularly stopped Cotto 6 months earlier. Prior to the bout, very few gave Mosley a chance of prevailing, with the prevailing view that Margarito was too strong and young for Mosley. The conventional wisdom was that this was a mismatch, which would end in a brutal retirement-forcing stoppage for "Sugar" Shane. A comparison of their last fights; the aforementioned destruction of Cotto by Margarito and a last-gasp knockout by Mosley in a hard twelve round struggle against Mayorga did not bode well for Mosley. Some predicted a massacre. And it was – only it was Margarito that was ruthlessly clubbed about the ring, unable to land any meaningful shots.
Mosley eventually TKO'd Margarito in the ninth round, after appearing to win every round up until then, in a massive upset. Sugar Shane utterly dominated Margarito, using his superior hand speed, pinpoint accuracy, consistent body punching, countless huge right hands to the jaw and tying up when Margarito backed him into the ropes, to wear Margarito down and stop him—something that many seasoned boxing observers thought was nigh-on impossible. After knocking him down with a series of heavy overhand rights at the end of the eighth round, Margarito was unable to avoid punches during a heavy barrage from Mosley early on in the ninth, forcing the referee to step in as Margarito slumped to the canvas a second time. Margarito had never previously been stopped. It was a sensational win for Sugar Shane and propelled him back to the upper echelons of the welterweight division and the sport of Boxing, in addition to further cementing his legacy as one of the best fighters in his era.
The fight was marred in a controversy after Mosley's trainer, Naazim Richardson diligently spotted a gauze knuckle pad accessory in Margarito's hand wraps, illegal because it had been previously used, which had to be redone three times before the commission's officials were satisfied.
The fight was for Margarito's WBA title and the vacant Lineal welterweight championship of Cyber Boxing Zone (CBZ). The Ring did not recognize this bout for its vacant welterweight championship despite the fact it pitted The Ring #1 ranked welterweight, Antonio Margarito, vs. The Ring #3 ranked welterweight, Shane Mosley. Coming in the bout, Margarito had just TKO'd the previous The Ring #1 ranked welterweight and current The Ring #2 ranked welterweight, Miguel Cotto. After the fight, Mosley was named The Ring's #1 ranked welterweight.
Mayweather vs Mosley
Main article: Floyd Mayweather vs. Shane Mosley
On May 1, 2010, Mosley fought undefeated Floyd Mayweather, Jr.. Boxing purists had called for the fight for over ten years. Mosley's WBA title was not on the line because Mayweather refused to pay WBA sanctioning fees. On the fight night, Mosley stunned Mayweather with two right-hand shots in the second round. Mayweather recovered well and dominated the remainder of the fight with superior reflexes and his effective counter-punching style, eventually beating Mosley in a wide decision on the scorecards to win Mosley's Lineal welterweight championship.
On May 22, 2010, Shane Mosley was stripped of his WBA (Super) welterweight title, due to not making a mandatory defense, which in turn made WBA Champion Vyacheslav Senchenko the sole WBA titlist in the welterweight division.
Mosley vs. Mora
Mosley at the Club Nokia in September 2010
Mosley fought Sergio Mora on September 18 at the Staples Center in Los Angeles. The bout ended up being a highly disputed split draw, where many people thought that Mosley narrowly won the closely contested bout (boxing analyst website Boxrec had it 114-112 for Mosley). The judges scored the bout: Mora 115–113, Mosley 116–112 and 114–114.
Pacquiao vs Mosley
Main article: Manny Pacquiao vs. Shane Mosley
On May 7, 2011, Mosley lost the fight to Manny Pacquiao for the WBO welterweight title at the MGM Grand in Las Vegas. Mosley was knocked down in round 3. Due to Mosley's defeat, Pacquiao looked at a November 12, 2011 match-up, a third fight with Juan Manuel Marquez.
Mosley announced he was coming out of retirement to fight Pablo Cesar Cano in Mexico. Mosley won the fight via unanimous decision with all three judges scoring the bout 115-113. Cano was able to win the first few rounds but Mosley took control of the later rounds and pounded Cano until the final bell, making Sugar Shane Mosley the vacant WBC International welterweight champion.
Mosley fought Australian boxer Anthony Mundine on November 27, 2013 at All Phones Arena in Sydney, Australia. Mosley lost the fight after Mundine scored a technical knockout during round 6. Before the seventh round, Mosley retiring due to back spasms giving Mundine the victory via TKO.
Mosley announced his second retirement on December 7, 2013. He stated that he plans to become a trainer, to train his son, Shane Jr., and other young fighters. In an interview with World Boxing News, when asked if he had any desire to lace up his gloves and return to the ring professionally, he said he would only consider a return to the sport against the very top welterweights in the world. He specifically named Floyd Mayweather Jr., Manny Pacquiao, and Juan Manuel Márquez. He also said in another interview in early 2015 that he was not sure if he would fight again, but that he wanted to come back and face a fighter of similar age and specifically named Juan Manuel Márquez.
On August 29, 2015, Mosley faced Ricardo Mayorga for second time, knocking out Mayorga again in the sixth round. On December 17, 2015, Mosley faced off against Venezuelan boxer Patrick Lopez in a 10 round Super Welterweight non-title match. Lopez was knocked down in the 2nd round and again ko'd in the last round to improve his record to 49 wins (41 KO victories).