Polyomaviruses are small DNA viruses present in mammals and birds, and in 1953 the first one to be described was murine polyomavirus. It was not until 1971 that the first two human polyomaviruses (HPyVs), BK virus and JC virus, were discovered and found to be common in humans, but only associated with disease in severely immunosuppressed patients. Since 2007, seven new HPyVs have been identified: KI polyomavirus, WU polyomavirus, Merkel cell polyomavirus, HPyV6, HPyV7, trichodyplasia spinulosa polyomavirus and HPyV9. Notably, Merkel cell polyomavirus was detected in Merkel cell cancer, a tumor mainly found in elderly and immunocompromised individuals, while trichodyplasia spinulosa polyomavirus was found in trichodyplasia spinulosa, a skin disorder observed only in immunosuppressed individuals. Consequently, many polyomaviruses cause problems in immunosuppressed individuals. This review deals with these issues, and the potential of the capsid protein VP1 to form virus-like particles for use as vaccines against polyomavirus infections.