From 1981 to 1984 he worked as a researcher at the biomedical institute of Leiden University before earning his PhD degree in mathematics and natural science in 1984.

[15] Plasterk was strongly criticized by the students unions for his proposals and by his coalition partners CDA and CU and the leftwing opposition parties SP and GroenLinks.

In the end he and Wouter Bos, the minister of Finance, were able to find sufficient money for a marked increase in the salaries of teachers.

[17] The Cabinet Balkenende IV fell on 20 February 2010 after tensions in the coalition over the extension of the Dutch involvement in the Task Force Urozgan of the International Security Assistance Force (ISAF) in Afghanistan and continued to serve in a demissionary capacity until the Labour Party cabinets members resigned on 23 February 2010.

[1][18] Following the election of 2012 Plasterk was appointed as Minister of the Interior and Kingdom Relations in the Cabinet Rutte II, taking office on 5 November 2012.

He did not succeed to merge the provinces of North Holland, Flevoland, and Utrecht and to reduce the memberships of provincial councils and executives.

He had to defend himself in front of the House of Representatives, when it was concluded the phone tapping had been performed by the Dutch General Intelligence and Security Service (AIVD).

[9] In his columns, he fiercely opposed the proposal of Maria van der Hoeven, who preceded him as minister of Education, to teach intelligent design in high schools.

He wrote that the Labour Party had lost touch with regular citizens, and he opined that the state of Dutch nature was not deteriorating during the nitrogen crisis in the Netherlands.

[22] In 1997 he coined the term ietsisme ("somethingism") to refer to the religious belief that the Christian God does not exist, but that there is some greater force that created the universe and governs it.

He first strongly criticized the belief on intellectual grounds, calling it a "poor and irritating phenomenon", but later claimed that it was a mix of atheism and nostalgia, and much more sympathetic "than the idea of a cruel God that wants this misery"[13] Following his retirement from national politics in October 2017, Plasterk continued his scientific work in the private sector.

While they were working on a scientific paper, Plasterk filed a patent for a method to develop personalized cancer treatments in July 2018, and he established a company called Frame Pharmaceuticals in December 2018.

His investors and shareholders were Dinko Valerio, Bob Löwenberg, and René Beukema, who had all earned their wealth through the sale of biotechnology company Crucell.

[24] Frame Pharmaceuticals received €1 million in subsidies to apply their personalized cancer treatments in partnership with Amsterdam UMC and the University Medical Center Groningen (UMCG).

[24] In November 2023, Plasterk was appointed scout during the 2023–2024 cabinet formation, and he later became informateur for a coalition consisting of the PVV, the VVD, NSC, and BBB.

[28][29] When the four parties reached a coalition agreement on 16 May 2024, national media outlets reported that Wilders had proposed Plasterk for the position of Prime Minister of the Netherlands.

[31] Two months earlier, newspaper NRC had chronicled Plasterk's scientific career in the private sector in the preceding years.

The NRC article noted that as Minister of Education, Culture and Science, Plasterk had successfully worked on a system to have researchers and universities share in profits resulting from their findings.

[32] Additionally, a criminal complaint for economic offenses and falsification of documents was filed by an attorney, who argued Plasterk had wrongfully referred to his company as a microbusiness in 2022.

[33] Plasterk withdrew himself as a candidate for prime minister on 20 May 2024, stating that the public perception of the accusations would hinder his ability to function effectively in the role.

Plasterk is a member of the Royal Christian Oratory Association "Excelsior" in Amsterdam, an evangelical[38] choir in which he sings as a tenor.