Fausto Gresini established the team in 1997 with Fabrizio Cecchini as technical director. The outfit began in the 500cc class with Brazilian rider Alex Barros on a Honda NSR500V two-cylinder machine. Barros recorded the team's first podium finish at Donington Park and placed ninth in the championship. The following year Honda upgraded Barros to the full NSR500 four-cylinder used by the factory team, and he collected 138 points for fifth overall.
In 1999 the team stepped down to the 250cc class with factory Honda support and reigning 250cc champion Loris Capirossi as rider. Capirossi won the opening round in Malaysia and added two further victories during the campaign, finishing third in the standings.
The team signed Daijiro Kato for the 2000 250cc season alongside Vincent Philippe. Kato delivered four consecutive podiums at the season's start and mounted a title challenge, ultimately finishing third with 259 points. The following year, rebranded as Telefónica Movistar Honda, Kato dominated the 250cc class with eleven victories to deliver the Gresini team their first World Championship title. Emilio Alzamora partnered Kato to a seventh-place finish overall.
In 2002 the team returned to the premier class, now renamed MotoGP, with Kato as sole rider. He rode the two-stroke Honda NSR500 for the first nine races before receiving the new four-stroke RC211V. Kato placed seventh in the championship and took Rookie of the Year honours.
The 2003 season brought tragedy. At the opening round at Suzuka, Kato crashed heavily and suffered severe injuries; he died in hospital two weeks later. Teammate Sete Gibernau, promoted to a factory-spec 2003 bike, won the South African Grand Prix at Welkom one week after Kato's death — dedicating the victory to his late colleague. Gibernau went on to win three further races and finished second in the championship.
Sete Gibernau remained the team's centrepiece through 2005, finishing runner-up in the championship again in 2004 alongside Colin Edwards. Marco Melandri joined for 2005 and proved consistently quick, taking race victories and challenging for the title. The 2006 season brought four victories between Melandri and new recruit Toni Elías, who returned the Fortuna tobacco sponsorship to the team's livery. Both riders remained for 2007, switching to Bridgestone tyres, but the new 800cc Honda RC212V underperformed relative to expectations and the team managed only two podiums.
Marco Simoncelli joined the team in 2010 as a satellite Honda rider and was elevated to factory-supported Honda machinery for 2011. Competitive but crash-prone, Simoncelli was announced to continue for 2012, but died following a racing accident at the Malaysian Grand Prix in October 2011.
In 2015 Gresini ended its long partnership with Honda in the premier class. Aprilia returned to MotoGP with a factory effort run by Gresini, who managed the squad's trackside operations. Aleix Espargaró scored the programme's first MotoGP-era podium at the 2021 British Grand Prix.
From 2022, Aprilia took full control of their factory operation, leaving Gresini to re-establish as a fully independent team with Ducati Desmosedici machinery. Enea Bastianini and Fabio Di Giannantonio formed the initial line-up. Bastianini made an immediate impact, winning four races across the season — including the Qatar opener — to finish third in the riders' standings, the best result for any Gresini rider in the MotoGP era to that point.
Bastianini was promoted to the Ducati factory team for 2023 and replaced by Álex Márquez. Di Giannantonio took the team's sole 2023 Grand Prix victory at Qatar, with Álex Márquez adding the team's first sprint victories. Di Giannantonio subsequently moved to VR46 Racing Team.
Marc Márquez joined Gresini for 2024 alongside his brother Álex, the first time siblings had been teammates at a top-tier motorcycle racing team since the Aoki brothers in 1997. Marc won three races — at Aragon, Misano, and Phillip Island — to finish third in the championship, and shared a podium with his brother at the German Grand Prix. He subsequently joined the Ducati factory team for 2025, replaced by Spanish rookie Fermín Aldeguer.
Gresini has competed in Moto2 since the category's inception in 2010, when Toni Elías won the inaugural Moto2 World Championship for the team riding a Honda-powered Moriwaki chassis. The Moto2 operation has continued under various title sponsorship arrangements, known for periods as QJmotor Gresini Racing before a sponsorship change in 2024.
Fausto Gresini founded the team after his retirement as a rider and led it until his death on 23 February 2021, following a two-month battle with COVID-19. His wife Nadia Padovani took over as team owner and principal, overseeing the transition to Ducati machinery and the team's emergence as one of the premier class's most competitive independent operations.