Human polyomaviruses are non-enveloped viruses with a circular double-stranded DNA genome of approximately 5,000 base pairs. The members BK virus and JC virus were first isolated in 1971 and are very common in the human population. Simian virus 40 (SV40), although originally isolated from rhesus macaques and accidentally introduced in the human population during massive poliovirus vaccination, may represent a third member of the polyomaviruses that can have man as a natural host. Primary infection with BK or/and JC virus occurs during early childhood. Subsequently, these viruses establish a seemingly life-long harmless latent infection. However, virus reactivation can occur especially in immunocompromised individuals and JC virus has been recognised as the cause of progressive multifocal leukoencephalopathy, while BK virus-associated interstitial nephritis has become an emerging complication in renal transplant patients. The genomes of human polyomaviruses encode two functional classes of proteins: the regulatory proteins large T-antigen, small t-antigen, and agnoprotein, and the structural proteins VP1, VP2 and VP3 that form the capsid. The regulatory proteins can modulate the expression and/or activity of cellular proteins involved in signal transduction, cell cycle regulation, and chromosomal functions. Therefore, they all possess oncogenic potential. Consistent with this, human polyomaviruses are capable of transforming human cells and inducing tumours in rodents, and are implicated in human malignancies. This book focuses on the etiological role of human polyomaviruses in cancer and highlights the mechanisms by which the viral regulatory proteins may contribute to neoplastic transformation of the infected host cells. Possible therapeutic strategies against these viruses will also be discussed.