[4] 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.

During this time, he worked as a domestique,[5] riding in support of varying team captains, even though the 2005 season saw Vande Velde taking chances of his own.

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.

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.

[9] 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.

[14] 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.

[15] Vande Velde finished a close second at the 2011 USA Pro Cycling Challenge, which was ultimately won by Levi Leipheimer (Team RadioShack).

[26][27] After the Tour de France, Vande Velde attempted to defend his USA Pro Cycling Challenge title,[28][29] however, he rode a quiet race, and finished twenty-second overall.

[35] 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.