[5] After a successful European 125cc campaign, in August 2002, Simoncelli made his first Grand Prix appearance with Matteoni Racing, replacing Czech rider Jaroslav Huleš who stepped up to the 250cc class.

[19][20] He joined the Metis Gilera team, an Italian motorcycle manufacturer who returned to the intermediate class after a lengthy absence.

He had his first 250cc win at the Italian Grand Prix held at Mugello on 1 June 2008 Barberá then crashed into him and Simoncelli won the race by 3 seconds.

Simoncelli obtained his third 250cc GP victory at the Sachsenring in the German Grand Prix on 13 July 2008 when he beat Bautista and Barberá by approximately 2.5 seconds.

He also won in his class at the 2008 Australian motorcycle Grand Prix held on 3–5 October 2008, narrowly defeating Bautista.

On 25 June 2009, it was confirmed that Simoncelli would move up to premier class racing for 2010 MotoGP championship after agreeing to ride with the San Carlo Gresini Honda team.

[22] Simoncelli got off to a slow start to the 2010 season, having suffered two preseason testing crashes at Sepang; the second of which cracked his helmet.

On 23 October 2011, Simoncelli was involved in a collision with American rider Colin Edwards and fellow Italian Valentino Rossi during the Malaysian Grand Prix at the Sepang International Circuit.

In fourth position during lap two, Simoncelli's bike lost traction in Turn 11 and it started to slide towards the gravel, but the tires regained traction and his bike suddenly veered across the track into the path of Edwards and Rossi, with Simoncelli hanging down on the right side;[33] Edwards and Rossi were unable to prevent collision.

[34][35][36][37] His body was flown home to Italy, accompanied by his father Paolo, his fiancée Kate Fretti, and Valentino Rossi.

The family were greeted by Italian Olympic Committee president Giovanni Petrucci, before the body was transported to a theatre in Coriano, Rimini, where it was placed in an open coffin.

Fans and visitors were then allowed to pay their respects, in a walk-through memorial that included his 250cc World Championship winning Gilera, plus his 2011 MotoGP Honda.

An estimated 20,000 people attended his funeral[38] at the Santa Maria Assunta parish church in Coriano on 27 October 2011, which was broadcast live on Italia 1 and Rai 2.

MotoGP riders Pecco Bagnaia, Franco Morbidelli, Luca Marini and Marco Bezzecchi are VR46 academy graduates.

At the 2012 Malaysian Grand Prix, Ferrari drivers Felipe Massa and Fernando Alonso, along with other members of the team paid tribute to Simoncelli by returning to turn 11 and having a group photo with a banner in remembrance.

[43] On the same day of the accident, all Serie A football matches in Italy held one minute of silence in remembrance of Simoncelli as instructed by the Italian National Olympic Committee President Gianni Petrucci.

CEO of Dorna Carmelo Ezpeleta led a ceremony of remembrance ahead of the Misano GP 2016 race weekend stating: "Today we say to Marco's father, Paolo, that from now this number belongs to the Simoncelli family.

(key) (Races in bold indicate pole position; races in italics indicate fastest lap) (key) (Races in bold indicate pole position, races in italics indicate fastest lap) (key) (Races in bold indicate pole position, races in italics indicate fastest lap) 1949  B. Ruffo 1950  D. Ambrosini 1951  B. Ruffo 1952  E. Lorenzetti 1953  W. Haas 1954  W. Haas 1955  H. Müller 1956  C. Ubbiali 1957  C. Sandford 1958  T. Provini 1959  C. Ubbiali 1960  C. Ubbiali 1961  M. Hailwood 1962  J. Redman 1963  J. Redman 1964  P. Read 1965  P. Read 1966  M. Hailwood 1967  M. Hailwood 1968  P. Read 1969  K. Carruthers 1970  R. Gould 1971  P. Read 1972  J. Saarinen 1973  D. Braun 1974  W. Villa 1975  W. Villa 1976  W. Villa 1977  M. Lega 1978  K. Ballington 1979  K. Ballington 1980  A. Mang 1981  A. Mang 1982  J. Tournadre 1983  C. Lavado 1984  C. Sarron 1985  F. Spencer 1986  C. Lavado 1987  A. Mang 1988  S. Pons 1989  S. Pons 1990  J. Kocinski 1991  L. Cadalora 1992  L. Cadalora 1993  T. Harada 1994  M. Biaggi 1995  M. Biaggi 1996  M. Biaggi 1997  M. Biaggi 1998  L. Capirossi 1999  V. Rossi 2000  O. Jacque 2001  D. Kato 2002  M. Melandri 2003  M. Poggiali 2004  D. Pedrosa 2005  D. Pedrosa 2006  J. Lorenzo 2007  J. Lorenzo 2008  M. Simoncelli 2009  H. Aoyama 2010  T. Elías 2011  S. Bradl 2012  M. Márquez 2013  P. Espargaró 2014  T. Rabat 2015  J. Zarco 2016  J. Zarco 2017  F. Morbidelli 2018  F. Bagnaia 2019  Á. Márquez 2020  E. Bastianini 2021  R. Gardner 2022  A. Fernández 2023  P. Acosta 2024  A. Ogura