With Slipstream–Chipotle’s team time trial win, Vande Velde became the first American to wear the pink jersey as leader of the general classification since Andrew Hampsten in 1988. Vande Velde finished the 2008 Tour de France in fourth place, 3’05” behind the winner Carlos Sastre, and seventeenth in the Olympic Road Race. In the 2009 Tour de France, Vande Velde finished seventh in the overall standings.

Vande Velde started his Grand Tour career by participating in the 1998 Vuelta a España, where he assisted Lance Armstrong, to a fourth-place finish. Vande Velde twice rode on the Tour de France team that brought Lance Armstrong to victory, in 1999, and 2001. In the 1999 Tour de France, Vande Velde was for a time the leader of the young rider classification; he did not compete, however, in the 2000 Tour de France. Vande Velde moved to Liberty Seguros in 2004, and switched to Team CSC in 2005. During this time, he worked as a domestique, riding in support of varying team captains, even though the 2005 season saw Vande Velde taking chances of his own. In one instance, Vande Velde was a breakaway participant on the fourth stage of the Eneco Tour. The breakaway, however, was eventually hampered when the peloton was led on a false route, meaning the breakaway riders had to wait for the peloton to get back on track, at which time the gap between the break and the peloton was reduced from six to four minutes with 43 kilometres to go.

At the 2006 Tour de Luxembourg, Vande Velde showed impressive performances in the mountains, which secured him first overall in the general classification.

In the 2006 Tour de France, he was a domestique on Team CSC for team captains Carlos Sastre and Fränk Schleck. Vande Velde was the best of the climbers in the team apart from Sastre and Schleck, whom he supported in the high mountain stages. On Stage 16, he pulled for most of the early slopes of the Col de la Croix de Fer, after which, team-mates Sastre and Schleck attacked to put then race leader Floyd Landis (Phonak) under pressure. On Stage 17, to Morzine, he again pulled for most of the day along with team-mates Jens Voigt, Matthias Kessler, and Serhiy Honchar from the T-Mobile Team.

Vande Velde crashed out of the 2010 Giro d’Italia on the third stage with a suspected clavicle break. Coincidentally, in 2009 he was forced out of the Giro after a crash, also on stage three. Vande Velde withdrew from the 2010 Tour de France upon completing the second stage, with two broken ribs. The crash was caused by oil leaking from a fallen television motorcycle.

During the 2011 Tour de France, Vande Velde assisted Tom Danielson to a top ten finish, and was an integral part of Garmin–Cervélo’s first place in the team classification. Vande Velde finished a close second at the 2011 USA Pro Cycling Challenge, which was ultimately won by Levi Leipheimer (Team RadioShack).

In the 2012 Giro d’Italia, Vande Velde was instrumental to the victory of his leader Ryder Hesjedal, protecting him in the mountain stages. He also was Hesjedal’s roommate during the Giro, and shared his thoughts about the race, and his teammate in an interview with Velo News, where he stated that winning the Giro was “surreal”. Suffering various crashes during the first week, Vande Velde, however, finished second in the fifteenth stage of the 2012 Tour de France, losing in a sprint to the finish to Frenchman Pierrick Fedrigo (FDJ–BigMat). NBC Sports commentator Phil Liggett stated that amongst fans, Vande Velde was considered the most popular rider. In the 2012 USA Pro Cycling Challenge, Vande Velde put in an impressive performance in the last stage’s individual time trial, finishing second to Taylor Phinney of BMC Racing Team by ten seconds. With that run, he took the leader’s jersey off the shoulders of Omega Pharma–Quick-Step’s Levi Leipheimer, and stepped atop the overall classification podium.

In a September 2012, online forum post, Garmin-Sharp team manager and owner Jonathan Vaughters stated that Vande Velde had used blood doping products to increase red blood cell production. On October 10, 2012, it was announced by USADA that he would be suspended for six months for admissions of doping during his time with the US Postal Cycling Team. Later that day a statement was released confirming his acceptance of a six-month ban from September 1, 2012, ending on March 1, 2013, along with a stripping of all race results between June 4, 2004, and April 30, 2006. Vande Velde released his own statement a day later that expressed regret at his decision to “cross the line”. “I’m very sorry for the mistakes I made in my past and I know that forgiveness is a lot to ask for. I know that I have to earn it and I will try, every day, to deserve it – as I have, every day, since making the choice to compete clean. I will never give up on this sport, and I will never stop fighting for its future.” he said.