The simian virus 40 and murine polyomaviruses were shown to be DNA tumor viruses in their natural hosts and/or heterologous experimental hosts in the mid-20th Century. The first two human polyomaviruses, the BK polyomavirus and JC polyomavirus, were discovered in 1971 and were shown to induce severe disease in immunocompromised patients, but their involvement in human cancers is still a matter for debate. The discovery of a polyomavirus associated with Merkel cell carcinoma (Merkel cell polyomavirus) in 2008 resulted in a renewed interest in the Polyomaviridae family, leading to the discovery of new human polyomaviruses. This review addresses the involvement of the nine human polyomaviruses and simian virus 40 in human diseases, with a particular focus on their prevalence and the humoral response directed against structural antigens in the general population and in subjects presenting specific diseases. © 2011 Future Medicine Ltd. ; Peer reviewed