Lorenzo made his World Championship debut on his fifteenth birthday at the 2002 125cc Spanish Grand Prix. He quickly rose through the ranks and became a dominant force in the 250cc class, winning the 2006 and 2007 championships with Aprilia. His 2007 season was particularly commanding, with nine pole positions leading to nine victories. His 16th victory in the 250cc class at Misano in 2007 made him the most successful Spanish rider of all time in the intermediate class, surpassing Dani Pedrosa and Sito Pons.
Lorenzo joined the factory Yamaha team in 2008 as Valentino Rossi's teammate and immediately demonstrated his potential, winning in Estoril to take his maiden MotoGP victory and earning the Rookie of the Year award while finishing fourth in the championship. Despite a season disrupted by multiple crashes and injuries, his speed was evident.
In 2009 Lorenzo improved to second in the standings, taking two victories but losing momentum mid-season. He secured his first MotoGP title in 2010 in commanding fashion, building a substantial lead through the first half of the season after Rossi suffered a broken leg at Mugello. He clinched the championship at Sepang with a third-place finish.
His second MotoGP title came in 2012, where he won five races including victories at Le Mans, Catalunya, and Mugello, claiming the crown at Phillip Island. In 2013, Lorenzo was narrowly beaten to the title by Marc Marquez by just four points, despite winning eight races — a testament to his consistency under pressure.
The 2015 season delivered Lorenzo's third MotoGP title and fifth world championship overall. He won seven races and was involved in one of the most dramatic title battles in recent memory, pipping teammate Valentino Rossi on the final day after Rossi was penalised and forced to start the Valencia Grand Prix from the back of the grid. Lorenzo won that race to take the championship by five points.
In 2016, Lorenzo set an all-time MotoGP record with his 65th career pole position and announced he would leave Yamaha for Ducati at season's end.
Lorenzo's transition to the Ducati Desmosedici in 2017 was difficult — he went winless for the first time in the premier class, finishing seventh. However, 2018 brought a remarkable turnaround. He won three consecutive races at Mugello, Barcelona, and the Red Bull Ring in Austria, demonstrating that he had finally mastered the different riding demands of the Italian machine. His Austria win was decided by just 0.130 seconds over Marc Marquez.
The move to Repsol Honda for 2019 proved ill-fated. Lorenzo suffered persistent injuries, including fracturing two vertebrae in a training crash at Assen, and never found his footing on the RC213V. He retired from racing on 14 November 2019 at Circuit Ricardo Tormo during the season finale, finishing the year 19th in the standings with 28 points — his worst season by a significant margin.
Lorenzo ranks fifth on the all-time list of premier class race winners with 47 victories from 203 starts, and third on the all-time podium list with 114 premier class podiums. During his nine seasons with Yamaha he won three championships and finished as runner-up three times. In 2016, his 64th career pole position set an all-time record at the time.
Known for his precise, ultra-smooth riding style and meticulous attention to corner entry and exit technique, Lorenzo was regarded as one of the cleanest technical riders in motorcycle racing history. His intense rivalry with Valentino Rossi — both teammates and fierce competitors — defined much of the Yamaha era in MotoGP.
After retiring from racing, Lorenzo served as a test rider for Yamaha in 2020 and 2021. He ventured into car racing, competing in the Porsche Carrera Cup Italia in 2022 and 2023, and signing a multi-year deal with Lazarus Corse to race an Aston Martin Vantage GT3 in the Italian GT Championship from 2024. He also provides color commentary for MotoGP broadcasts in Spain on DAZN. In 2022, the FIM inducted him into the MotoGP Hall of Fame as an official Legend.