Fausto Gresini, born in 1961, founded the team in 1997 alongside technical director Fabrizio Cecchini. The outfit immediately entered the 500 cc class with Brazilian rider Alex Barros and a Honda NSR500V two-cylinder, claiming its first podium at Donington Park. Honda subsequently upgraded Barros to a four-cylinder NSR500 for 1998, netting him two podiums and fifth in the championship.
The team dropped to the 250 cc class in 1999 with factory Honda NSR250 machinery and reigning champion Loris Capirossi, who opened the season with victory in Malaysia — the team's first win. When Capirossi stepped up, the team signed Daijiro Kato alongside Vincent Philippe for 2000. Kato's 259 points and third in the championship earned him Rookie of the Year. The squad was renamed Telefónica Movistar Honda for 2001, and Kato dominated, winning 11 races to deliver Gresini their first world title. Emilio Alzamora contributed two podiums as well.
Gresini brought Kato to MotoGP in 2002 as Fortuna Honda Gresini. Kato rode the old NSR500 for the first nine races before receiving the new RC211V at Brno, promptly matching his best with second place in his first four-stroke race. He ranked seventh and won Rookie of the Year.
In 2003 the team expanded to two riders, adding Sete Gibernau alongside Kato. In the opening race at Suzuka, Kato crashed heavily into a tyre barrier. He fell into a coma and died in hospital two weeks later. A week after his death, Gibernau won the South African Grand Prix at Welkom — dedicating the victory to his late teammate. Gibernau went on to win three more races and finished second in the championship that year.
Gibernau fought for the championship again in 2004, finishing runner-up with Colin Edwards fifth. In 2005 and 2006 Marco Melandri was a central figure, winning twice in 2005 and three times in 2006. Toni Elías, who brought Fortuna sponsorship, added a further victory in 2006. The team's results declined with the shift to 800 cc machinery and a change to Bridgestone tyres in 2007, and further with roster turnover in 2008 and 2009.
Marco Simoncelli joined as a factory Honda rider in 2011 alongside Hiroshi Aoyama. Simoncelli showed front-running pace but crashes cost him points. On 23 October 2011, Simoncelli died after a racing accident at the Malaysian Grand Prix.
In 2015 Gresini ended its Honda relationship and began operating as Aprilia's factory MotoGP partner, managing trackside operations for the Italian manufacturer's works effort. Aleix Espargaró scored the first MotoGP-era podium for Aprilia during the 2021 British Grand Prix.
When Aprilia re-entered as a fully autonomous factory team for 2022, Gresini chose to become an independent team once more, taking Ducati machinery and fielding Enea Bastianini and Fabio Di Giannantonio. Bastianini secured the team's first-ever premier-class victory at the Qatar Grand Prix and added wins in the United States, France, and Aragon. He finished third in the riders' championship and was promoted to the Ducati factory team for 2023, replaced by Álex Márquez.
Marc Márquez joined for 2024 after eleven years with Repsol Honda, pairing with his brother Álex. The brothers shared a podium at the German Grand Prix — a sibling feat not seen since the Aoki brothers in 1997. Marc took three victories that season at Aragon, Misano, and Phillip Island, finishing third in the championship.
Fermín Aldeguer replaced Marc Márquez for 2025, with the older Márquez joining the Ducati works team. Álex Márquez took his maiden Grand Prix victory at Jerez, while Aldeguer claimed his at the Indonesian Grand Prix — making him the first independent-team rookie winner since Martín in 2021. The team clinched the independent team of the year title at the Malaysian Grand Prix, with Álex Márquez securing runner-up in the riders' championship.
Fausto Gresini died on 23 February 2021 after a two-month battle with COVID-19. His wife, Nadia Padovani, assumed the role of team owner and principal, steering the team through its most successful MotoGP period to date.