In 2000, Miami underwent an overhaul to attempt to put together the pieces to win a championship, and expectations leading up to the season were high. However, prior the start of the 2000-01 season, Mourning was diagnosed with focal segmental glomerulosclerosis, a disease of the kidneys, that had caused him to miss the first five months of that season. Even after the diagnosis, Mourning returned and played in the 2002 NBA All-Star Game. Because his condition worsened, Mourning did not play during the entire 2002-03 season and his expiring contract was not renewed by the then-rebuilding Heat.

As a free agent, in 2003 he signed a four-year contract with the New Jersey Nets. But on November 25, 2003 Mourning retired from the NBA due to complications from his kidney disease. On December 19 of that year he underwent a successful kidney transplant. In 2004, he started practicing with the Nets again, and made the team's regular season roster for a part of his time spent with the Nets in the 2004-05 season. However, he did not play a significant role with the Nets and openly complained to the media that he wanted out of New Jersey, especially after the team traded Kenyon Martin.  Mourning was traded to the Toronto Raptors on December 17, 2004. Mourning never reported to the Raptors as he was bought out of his contract, at a remaining 9 million dollars, on February 11, 2005.Raptors team officials later said that he did not meet the medical conditions to play for the team. Mourning then finished the season with the Miami Heat being paid a second salary, the veteran's minimum.

After being unhappy at the prospect of playing for a losing franchise, Mourning re-signed with the Heat on March 1, 2005. his intensity had earned him the title "The Ultimate Warrior" amongst Miami Heat fans. Mourning finished the regular season ranking third in blocked shots at 2.66 per game, despite only playing 20 minutes per contest.

The Miami Heat and Mourning finally won the elusive NBA Championship in the 2006 NBA Finals against the Dallas Mavericks 4 games to 2.

After winning the championship, Mourning announced that he would return to the Heat in 2006-07 to defend their title, despite receiving offers of more money from other teams, including the San Antonio Spurs. In 2007, Mourning announced he would return for one more year with the Heat and his 15th season. "It will definitely be my last year", Mourning said. After starting the season on a solid note averaging 6 points, 3.8 rebounds and 1.75 blocks in just over 16 played per 24 games, Mourning tore his patellar tendon in his right knee on December 19 during the first quarter of a 117-111 OT loss in Atlanta. The injury, which occurred on the fourth anniversary of his successful kidney transplant, was said to be career-threatening, but rumors have persisted about a return come the 2008-2009 season, and Mourning himself said that this wasn't the way he wanted to end his career considering all he had been through already.

Currently Mourning has averaged the most blocks in the NBA per 48 minutes with 5.46.