In 2007 Mollema won the prestigious stage race for upcoming talents Tour de l'Avenir and the Circuito Montañés.

He made his ProTour debut in the Tour de Romandie, but did not finish the race due to a fall, which resulted in a fractured collarbone.

He fully returned in top shape in the Deutschland Tour, in which he started as Rabobank's team leader, eventually finishing 7th in the overall general classification.

Mollema made his Grand Tour debut in the 2010 Giro d'Italia in which he made a good impression but fell short of a top 10 classification and winning the young rider competition, partially due to missing out on a break-away of 50 riders in which a lot of direct opponents gained a 12-minute lead.

Mollema continued to ride strong later in the season with a mountain stage win in the Tour de Pologne and a third place overall after winner Dan Martin and runner-up Grega Bole.

He did not lose any crucial time in the first week and was awarded the red leader's jersey after his second place in stage 9.

Due to his weaker time trial skills compared to other general classification contenders such as Bradley Wiggins, Chris Froome and Vincenzo Nibali, he lost the leader's jersey a day after he had won it.

Mollema rode well after the time trial and was heading for a podium position, but he fell to fourth place overall due to the performance of Juan José Cobo on the Alto de l'Angliru.

He won Stage 17 of the race by attacking from the peloton 500 metres (1,600 feet) from the line, and holding off the chasing pack led home by Edvald Boasson Hagen (Team Sky).

[12] At the Tour de France, Mollema sat seventh overall heading into the penultimate stage, an individual time trial 54 kilometres (34 miles) in length.

However, riding a new Bianchi for the first time, Mollema could only place in 140th position and slipped to tenth overall in the general classification, 21 minutes and 24 seconds behind the winner, Vincenzo Nibali.

[16] Mollema finished seventh overall in the Tour de France, having moved definitively into the top ten overall at the midway point of the race.

[18] In the early part of the season, Mollema finished in third place overall at the Vuelta a Andalucía,[19] moving up from fourteenth on the final stage.

[26] In his third season with Trek–Segafredo, Mollema opted to ride the general classification at the Giro d'Italia, as Alberto Contador rode the Tour de France as team leader.

[33] Even though he had ridden two Grand Tours during the season, he started in Clásica de San Sebastián a week later and finished in third place,[34] his third podium at the race.

In October he won the Italian semi classic Gran Premio Bruno Beghelli, attacking from just over 2 kilometres (1.2 miles) from the finish,[45] for his second victory of the season.

[53][54] Following the World Championships, Mollema took two individual victories in October: the first of these came in the final cycling monument of the season, Il Lombardia.

With approximately 18 kilometres (11 miles) remaining, and on the penultimate climb, Mollema made a solo move and held off his closest rivals – Alejandro Valverde, Egan Bernal and Jakob Fuglsang – by sixteen seconds to take the victory, and his first monument.

[65] Mollema started the 2021 season with a block of short stage races in France, finishing sixth overall at the Tour de la Provence,[66] and at the Tour des Alpes-Maritimes et du Var, Mollema won a stage, finished third overall and won the points classification.

[67][68] Mollema then contested several one-day races in Italy, taking a victory at Trofeo Laigueglia after a 15-kilometre (9.3-mile) solo move,[69] and then finished second to Mauri Vansevenant in a small group sprint at the GP Industria & Artigianato di Larciano.

[73] He took top-ten finishes on each of the first two stages at the Tour de France, before falling towards the bottom of the top twenty placings by the end of the first week.

[75] His next start came in the road race at the COVID-19 pandemic-delayed Tokyo Olympics, where he sprinted in the group contesting the minor medals behind winner Richard Carapaz, but missed out in fourth place.

[83][84] He finished in fourth place at August's Clásica de San Sebastián, and missed out on a victory in the prologue of the Deutschland Tour by two seconds to Filippo Ganna.

[85][86] The Netherlands missed out on a medal in the mixed team relay for the first time at the UCI Road World Championships, with Mollema suffering a mechanical and the second of two incidents where he was attacked by a magpie while riding (the first having occurred during training).

He was not selected by the renamed Lidl–Trek team for the Tour de France, ending a twelve-year consecutive starts streak at the race.