Valentino Rossi has played a vital role in developing the YZR-M1 and their love story is one of the most famous tales in the world of motorsport. The Doctor first tested the YZR-M1 in 2004 and tried multiple engine prototypes before choosing one that he labeled a "sweet" engine. The story between Rossi and the M1 machine reached epic heights when he won his debut race on the Yamaha in Welkom (South Africa) that same season. He went on to win four MotoGP championships in nine seasons racing with it.

For the 2021 season the YZR-M1 carries lightning fast newcomer Fabio Quartararo, with Franco Morbidelli joining in the final stages of the campaign at the Monster Energy Yamaha MotoGP Team, with Rossi and Andrea Dovizioso forming Petronas Yamaha SRT Team's star-studded line-up.