Polyomaviruses are ubiquitous agents that infect mammals and birds. At least 14 distinct species are known to infect humans. Infections caused by these viruses are quite common, and most infections are completely asymptomatic. The first two human-tropic polyomaviruses discovered, JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV), cause the most morbidity. JCPyV is associated with the development of progressive multifocal leukoencephalopathy in immunocompromised individuals, and BKPyV is a well-recognized cause of nephropathy, particularly in renal transplant recipients. Both viruses enter a dormant state following the primary infection. Associated morbidity is seen when the dormant agents become reactivated in immunocompromised hosts. Safe and effective therapies for symptomatic disease remain elusive. When feasible, reducing or stopping immune suppression therapies can be effective in improving outcomes.