Schleck's greatest achievements include five national road race championships, winning the Queen stage of the 2006 Tour de France, which finished on the Alpe d'Huez, the 2006 edition of the Amstel Gold Race classic, and an alpine stage of the 2009 Tour de France, finishing in the sole company of his brother Andy and Alberto Contador.

On 30 January 2013, Schleck was suspended for 12 months following a positive test for xipamide at the 2012 Tour de France.

Sitting with the favorites with ten kilometers to go, Schleck broke away alone up the Cauberg in Valkenburg for a solo finish while teammate Karsten Kroon disrupted the chase.

Three days later he finished 4th in La Flèche Wallonne after a vigorous ride up the Mur de Huy where Spanish rider Alejandro Valverde proved unbeatable.

In the Tour de France, he won stage 15 from Gap to Alpe d'Huez, where he broke away from Damiano Cunego 1.5 km from the finish.

Schleck won the fourth stage of the Tour de Suisse, taking the yellow jersey; he eventually finished 7th.

Only two riders were able to follow the two brothers when they attacked on the final hills of the day: Alejandro Valverde and Davide Rebellin.

Eight days later Schleck took the yellow jersey as leader of the general classification after claiming the single second he needed to pass Cadel Evans.

On 19 April, while attempting to repeat his winning 2006 Amstel Gold Race effort, Schleck crashed badly together with Matthew Lloyd.

[6] Schleck made a rapid recovery, winning his home race, the Tour de Luxembourg, in June.

On 22 July he won the 17th stage of the Tour de France, reaching the finish line in the company of overall leader Alberto Contador and his own brother, Andy Schleck.

[8] For the 2011 season, Frank's new team was confirmed as Leopard Trek and Schleck won the Critérium International, before achieving a podium finish at Liège–Bastogne–Liège, and defending his Luxembourg National Road Race title.

Schleck left the Tour de France after the Union Cycliste Internationale (UCI) revealed he had tested positive for the banned substance diuretic xipamide.

[11] After Trek Bicycles purchased the World Tour licence of the RadioShack–Leopard squad later in the month, it was announced that Schleck would be signed by the team for the 2014 season.

[16] On 25 July 2008, one day prior to a decisive penultimate stage of the 2008 Tour de France, the German daily newspaper Süddeutsche Zeitung alleged contact between Schleck and the infamous Spanish doctor Eufemiano Fuentes in December 2005.

[17] The allegations in connection with Schleck followed a series of strong performances by the rider, who had worn the yellow jersey for several days.

On 17 July 2012, Schleck was removed from the 2012 Tour de France by his team RadioShack–Nissan during the second rest day after his A-sample returned traces of the diuretic Xipamide.