Polyomaviruses are small, nonenveloped DNA viruses, which are widespread in nature. In immunocompetent hosts, the viruses remain latent after primary infection. With few exceptions, illnesses associated with these viruses occur in times of immune compromise, especially in conditions that bring about T cell deficiency. The human polyomaviruses BKV and JCV are known to cause, respectively, hemorrhagic cystitis in recipients of bone marrow transplantation and progressive multifocal leukoencephalopathy in immunocompromised patients, for example, by HIV infection. Recently, transplant nephropathy due to BKV infection has been increasingly recognized as the cause for renal allograft failure. Quantitation of polyomavirus DNA in the blood, cerebrospinal fluid, and urine, identification of virus laden "decoy cells" in urine, and histopathologic demonstration of viral inclusions in the brain parenchyma and renal tubules are the applicable diagnostic methods. Genomic sequences of polyomaviruses have been reported to be associated with various neoplastic disorders and autoimmune conditions. While various antiviral agents have been tried to treat polyomavirus-related illnesses, current management aims at the modification and/or improvement in the hosts' immune status. In this chapter, we provide an overview of polyomaviruses and briefly introduce its association with human diseases, which will be covered extensively in other chapters by experts in the field.