In a sport rife with cheaters, Armstrong has been under constant suspicion since the 1990s from those who refused to believe he was a clean rider winning cycling's premier event against a field of doped-up competition.
He had tense public disputes with USADA, the World Anti-Doping Agency, some former teammates and assistants and even Greg LeMond, the first American to win the Tour de France.
Through it all, Armstrong vigorously denied any and all hints, rumors and direct accusations he was cheating. He had the blazing personality, celebrity and personal wealth needed to fight back with legal and public relations battles to clear his name - and he did, time after time.
Armstrong won his first Tour at a time when doping scandals had rocked the race. He was leading the race when a trace amount of a banned anti-inflammatory corticosteroid was found in his urine; cycling officials said he was authorized to use a small amount of a cream to treat saddle sores.
After Armstrong's second victory in 2000, French judicial officials investigated his Postal Service team for drug use. That investigation ended with no charges, but the allegations kept coming.
Armstrong was criticized for his relationship with Ferrari, who was banned by Italian authorities over doping charges in 2002. Former personal and team assistants accused Armstrong of having steroids in an apartment in Spain and disposing of syringes that were used for injections.
In 2004, a Dallas-based promotions company initially refused to pay him a $5 million bonus for winning his sixth Tour de France because it wanted to investigate allegations raised by media in Europe. Testimony in that case included former teammate Frankie Andreu and his wife, Betsy, saying Armstrong told doctors during his 1996 cancer treatments that he had taken a cornucopia of steroids and performance-enhancing drugs.
Two books published in Europe, "L.A. Confidential" and "L.A. Official," also raised doping allegations and, in 2005, French magazine L'Equipe reported that retested urine samples from the 1999 Tour showed EPO use.
Armstrong fought every accusation with denials and, in some cases, lawsuits against the European media outlets that reported them.
But he showed signs that he was tiring of the never-ending questions. Armstrong retired (for the first time) in 2005 and almost immediately considered a comeback before deciding to stay on the sidelines, in part, because he didn't want to keep answering doping questions.
"I'm sick of this," Armstrong said in 2005. "Sitting here today, dealing with all this stuff again, knowing if I were to go back, there's no way I could get a fair shake - on the roadside, in doping control, or the labs."
Three years later, Armstrong was 36 and itching to ride again. He came back to finish third in the 2009 Tour de France.
Armstrong raced in the Tour again in 2010, under the cloud of the federal criminal investigation. Early last year, he quit the sport for good, but made a brief return as a triathlete until the USADA investigation shut him down.
During his sworn testimony in the dispute over the $5 million bonus, Armstrong said he wouldn't take performance enhancing drugs because he had too much to lose.
"(The) faith of all the cancer survivors around the world. Everything I do off the bike would go away, too," Armstrong said then. "And don't think for a second I don't understand that. It's not about money for me. Everything. It's also about the faith that people have put in me over the years. So all of that would be erased."