On October 26, 2013, Spies announced his retirement from motorcycle racing after two debilitating crashes left him with permanent shoulder injuries.

Again with Valvoline Suzuki in 2001, Spies won the Pikes Peak round of the AMA 750 SuperStock Championship, and took four additional series podium finishes.

Now with American Suzuki team, Spies won the 2003 AMA Formula Xtreme Championship with five wins and two additional podium finishes.

He also contested the AMA Supersport series, earning a win at Road Atlanta and taking two additional podium finishes.

In 2005 Spies won the AMA Superbike race at California Speedway and earned 13 additional podium finishes.

Spies also raced in select AMA Supersport events, earning a podium finish at Mazda Raceway Laguna Seca.

[7] In 2008 Spies won his third straight AMA Superbike Championship to become only the fourth rider in the history of the series to win the title three consecutive times (after Reg Pridmore, Fred Merkel and Mat Mladin, who accomplished the feat twice).

On October 1, 2008, it was confirmed that Spies would join the Superbike World Championship for the 2009 season, riding for the factory Yamaha Italia team.

[10] Two days later it was confirmed that Spies would ride as a wildcard for the Yamaha Sterilgarda team, in the final MotoGP race of the season at Valencia in November,.

[12] Spies started the season with fifth place at Losail, his best ever on a MotoGP bike, before retiring in the next two races with a mechanical problem at Jerez and a crash at Le Mans.

Spies moved to the factory Yamaha Motor Racing Team alongside 2010 champion Jorge Lorenzo, replacing the Ducati bound Valentino Rossi in 2011.

Having qualified second, Spies made contact on the first lap with Dovizioso, and as a result, fell to as low as ninth place before making several late braking moves to progress through the order.

[19] However, his injuries forced him to pull out on race morning, and were also a factor in his similar withdrawal from the Malaysian Grand Prix, having qualified 16th out of the 17 riders and after two further practice crashes.

Spies placed eleventh in the first two races of the season in Qatar and Jerez, before taking his first top ten with eighth in Portugal.

He retired from each of the following three races, before taking a pair of fifth-place finishes at the Grands Prix in San Marino and Aragon.

An issue with his bike's brakes forced a retirement in Japan,[22] while he crashed out in Malaysia; he suffered injuries in the accident which ruled him out for the rest of the season.

On July 24, it was announced that Spies would leave the factory Yamaha team at the end of the 2012 season, making way for the returning Valentino Rossi.

[24] On September 12, it was announced that Spies would remain in MotoGP for the 2013 season, joining the satellite Pramac Racing Ducati squad as part of a two-rider team alongside Moto2 graduate Andrea Iannone.