In Stage 16 of the Tour de France, Gilbert was involved in a spectacular crash in a downhill section where he went over a wall, suffering lacerations and fracturing his kneecap. This was the same road where Fabio Casartelli died in the 1995 Tour de France. Gilbert climbed back onto his bike and rode the remaining 57 kilometres (35 mi) to the finish in Bagnères-de-Luchon, earning him the Most Combative Rider award but ending his tour.

Born in Remouchamps in the municipality of Aywaille, Gilbert turned professional in 2003 by joining FDJeux.com after riding as stagiaire for the team in late 2000. During this season he recorded his first victory by winning a stage in the Tour de l’Avenir. In 2004 he began by winning a stage in the Tour Down Under as well as the young rider classification. He participated in the Cycling at the 2004 Summer Olympics – Men’s individual road race at the 2004 Summer Olympics where he finished 49th. He also won the Paris–Corrèze. In 2005 he won several races in France, which allowed him to win the Coupe de France de cyclisme sur route. These victories included the Trophée des Grimpeurs, the Tour du Haut Var and the Polynormande. He also took stages in the Four Days of Dunkirk and the Tour Méditerranéen.

2006 would become his most successful year to the point when he won the prestigious Omloop Het Volk after repeatedly attacking until he got away alone with 7 kilometres (4.3 miles) to go. During the season he also won the Grand Prix de Fourmies and the Grand Prix de Wallonie as well as stages at the Critérium du Dauphiné Libéré and the Eneco Tour.

In early 2007 he had a skin cancer lesion removed from his thigh, delaying the start of his season. That did not stop him from trying himself during Milan–San Remo, where he managed to escape on the Poggio with Riccardo Riccò before being captured 1.2 kilometres (0.75 miles) from the finishing line. He could not get any victory during the season until the Tour du Limousin, where he claimed his only victory in 2007 by winning a stage. In Paris–Tours he was caught with 500 metres (1,600 feet) to go along with Karsten Kroon and Filippo Pozzato.

Gilbert started 2008 by winning the King of the Mountains competition at the Tour Down Under and the overall classification as well as two stages of the Vuelta a Mallorca. He also finished third in Milan–San Remo, accomplishing his first podium in a monument. He later won Omloop Het Volk for the second time in his career after a solo attack with almost 50 kilometres (31 miles) to go. Four days later he won the GP Samyn. He finished the year by winning the classic Paris–Tours race in a late breakaway where he won a sprint between his three breakaway companions. The peloton finished four seconds back.

In 2009 he joined Silence–Lotto to lead the Belgian team in the classics, finishing third at the Tour of Flanders and fourth in both the Amstel Gold Race and Liège–Bastogne–Liège. He also took his first stage in a Grand Tour by winning the 20th stage of the Giro d’Italia and won a stage and the overall classification of the Ster Elektrotoer. Later in the season he repeated his Paris–Tours win, attacking on the last climb with Tom Boonen and Borut Božič before outsprinting them to the line. A week later, he also won the prestigious Giro di Lombardia after escaping from the peloton with Samuel Sánchez, beating him to the finish by a half-length. It was his fourth victory in 10 days after also winning the Coppa Sabatini and Giro del Piemonte. At the end of the season he was awarded the Flandrien of the Year award, recognising him as the best Belgian rider of the year.

In 2010 he won his first classic of the year, April’s Amstel Gold Race. After an aggressive race featuring many attacks, he won through a big attack in the last 500 metres (1,600 feet) of the climb to the finish, comfortably winning by several bike lengths from the peloton. He also won the first stage of the Tour of Belgium. Gilbert then ended the 2010 season in superb form. He followed up two stage wins in the Vuelta a España with victories in the Giro del Piemonte and the Giro di Lombardia, repeating his 2009 wins in both races. The Giro di Lombardia was won with a solo attack in atrocious weather conditions.

In 2011, Gilbert won the Montepaschi Strade Bianche, a race including 70 kilometres (43 miles) of gravel roads. He then had a quadruple consecutive win: first he won the Brabantse Pijl, then he repeated as winner of the Amstel Gold Race, breaking free on the Cauberg. Three days later, he won La Flèche Wallonne dropping his rivals on the final climb of the Mur de Huy and finally he won Liège–Bastogne–Liège beating the Schleck brothers in the sprint. Gilbert thus became the second rider, after Davide Rebellin in 2004, to win the three Ardennes classics in a single year. During the first half of the season he also won stages at the Volta ao Algarve, Tirreno–Adriatico as well as the overall classification and a stage of both the Tour of Belgium and Ster ZLM Toer.

Gilbert was appointed as a member of the inaugural UCI Athletes’ Commission in 2011.

In 2012, Gilbert signed for BMC Racing Team on a three-year contract reportedly worth €3 million a year. His goals for his new squad were to perform highly in the Spring classics and help his team-mate Cadel Evans repeat his 2011 feat of winning the Tour de France. Neither of those came to fruition, as Gilbert’s best result in the one-day spring races was third at La Flèche Wallonne, where he got deposited on the final climb by Joaquim Rodríguez who won atop the historic Mur de Huy with a slim margin of 4 seconds. Three days prior, he took sixth position at the Amstel Gold Race and was pleased to achieve a top ten ranking in the Ardennes race. He missed out on his goal to bring Evans in yellow to Paris and his best placing in a Tour de France stage was fourth. He also lost both of the Belgian National Championship titles he held, finishing third in the Belgian National Time Trial Championships.

On 26 August 2012, Gilbert finally managed his first victory of the season by winning the ninth stage of the Vuelta a España after breaking away together with Rodríguez. He later won a second stage of the race, winning stage nineteen on 7 September.

On 23 September 2012, Gilbert won the UCI Elite Men’s Road Race world championship and the rainbow jersey, ahead of Edvald Boasson Hagen and Alejandro Valverde by producing a massive surge on the final climb of the Cauberg.

In 2013, Gilbert headed towards the World Championships without a single win in the rainbow jersey, in danger of his first winless season since turning professional in 2003. He started the Vuelta a España hoping that the competition would, for the second successive year, kick-start his season. After being narrowly defeated in a sprint by Zdeněk Štybar on stage 7, Gilbert finally clinched a victory in the rainbow stripes when he caught and passed Edvald Boasson Hagen to win stage 12.

In 2014, Gilbert picked up his previous form when in the spring he won his second Brabantse Pijl and his third Amstel Gold Race.

In August 2019, Gilbert signed a three-year contract with the Lotto–Soudal team from the 2020 season onwards.