At PSV he won the Johan Cruijff Shield in 2008 and the KNVB Beker in 2011–12 and also became a regular member of the Dutch national team.

Born in Tiel, Pieters grew up in Enspijk and started as a central midfielder in the juvenile ranks of VV Rhelico in Rumpt.

In 2008–09 Pieters played 23 times for PSV as they finished in 4th position, winning the 2008 Johan Cruijff Schaal by beating Feyenoord 2–0.

The following season, Pieters regained his place in the starting eleven and played his part as PSV went on an unbeaten run for the last two months leading up to the winter break.

[10] He made his return from injury in a league match against PEC Zwolle on 18 January 2013 after a nine-month layoff, and with PSV losing 3–1 Pieters was sent-off for a foul on Fred Benson.

Such was Pieters' anger that he ran down the players entrance and punched a window, badly cutting his arm and was ruled out for a further three months.

[16][17] Pieters scored his first goal for Stoke on 12 April 2014 in a 1–0 win over Newcastle United after his intended cross beat Tim Krul.

[20] Pieters retained his place at left-back under Mark Hughes in 2014–15, playing in 32 matches as Stoke finished in ninth position.

[25] At the end of the season Opta Sports revealed that Pieters made more tackles than any other defender in the Premier League during the campaign.

[29][30] Pieters was fined £70,000 by manager Paul Lambert in March 2018 after attending a late night party just hours before a league fixture against Everton.

[37] On 13 September 2022, Pieters joined EFL Championship club West Bromwich Albion on a free transfer, signing a deal until the end of the season.

In the semi-finals against England (1–1, 13–12 after 32 penalty kicks), Pieters played in the starting eleven, but was later substituted by Tim Janssen to improve the attack as well as due to a small injury.

On 7 May 2012, Pieters was named in the provisional list of 36 players for the Euro 2012 tournament, but he did not recover in time for the competition due to a foot injury.