This article traces the discovery of polyomaviruses and outlines investigations, which shed light on potential modes of transmission of this increasingly important group of human pathogens. The pathobiology of the virus is summarized with particular reference to interactions with host cell receptors, cell entry, cytoplasmic trafficking, and targeting of the viral genome to the nucleus. This is followed by a discussion of sites of viral latency and factors leading to viral reactivation. Finally, we present biochemical mechanisms that could potentially explain several key elements of tissue pathology characteristic of BKV mediated damage to human kidney.