Polyomaviruses were originally isolated in mouse and in monkey (SV40) about 50 years ago. In 1971, the first human polyomaviruses BK and JC were isolated and subsequently demonstrated to be ubiquitous in the human population. Recent studies have shown that SV40 can spread between humans and led to the identification of three new human polyomaviruses (KIPyV, MCPyV, and WUPyV). BKV, JCV, and SV40 appear harmless in healthy individuals, but possess pathogenic properties in immunosuppressed patients. Moreover they may play an etiological role in human malignancies. Epidemiologic and pathogenic studies of KIPyV, MCPyC, and WUPyV are limited so far, but MCPyV may be associated with Merkel cell carcinoma, a rare but aggressive neuroendocrine skin cancer. We describe the biology of human polyomaviruses, review their nonmalignant and malignant potentials, and discuss the mechanisms by which these viruses may contribute to transformation.