Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals. For nearly 40 years, only two polyomaviruses were known to infect humans. Genome sequencing technologies have recently discovered seven additional human polyomaviruses, including one causing most cases of Merkel cell carcinoma and another associated with transplant-associated dysplasia (TSV), that are natural infections of humans. Discovery of these polyomaviruses and other new--but previously undiscovered-viruses may provide clues to the etiologies for human diseases. Polyomaviruses have been extensively studied as tumor viruses in humans and animals, leading to fundamental insights into carcinogenesis, DNA replication and protein processing. The tumor suppressor molecule p53 was discovered, for example, as a cellular protein bound by the major oncoprotein (cancer-causing protein) T antigen made by Simian vacuolating virus 40 (SV40). The avian polyomavirus sometimes referred to as the Budgerigar fledgling disease virus is a frequent cause of death among caged birds. Middle T antigen (MT) is a 421-amino-acid protein associated with membranes and underlying cytoskeletal elements, and is associated with a tyrosine-specific protein kinase activity. It is the principal oncoprotein of polyomavirus that is necessary and often sufficient for transformation in vitro. MT delivered as a transgene or a retrovirus can induce tumors in a wide variety of tissues. Polyomavirus (PyV) is a small, double-stranded, closed-circular-DNA virus with an approximately 5-kb genome divided into two roughly equal regions. The late transcripts produce the viral capsid proteins, whereas the early region encodes three so-called tumor (T) antigens that are important for both productive infection and transformation.