Kaposi sarcoma-associated herpesvirus (KSHV) is a recently discovered and characterized member of the herpesvirus family. It is one of a few viruses proved to be associated with tumorigenesis in humans. Its causal association with 4 clinical and epidemiologic variants of Kaposi sarcoma (classic, endemic, iatrogenic, and acquired immunodeficiency virus-associated) as well as with several lymphoproliferative disorders (notably primary effusion lymphoma and multicentric Castleman disease) is reviewed critically. Issues related to the epidemiology, transmission, and molecular and serologic diagnosis are discussed. Several intriguing oncogenic mechanisms of KSHV infection have been identified. These are often dependent on the interaction of KSHV with other viruses, such as human immunodeficiency virus, Epstein-Barr virus, or both. However, important problems remain and once resolved will substantially enhance our understanding of oncogenesis in general and viral-induced oncogenesis in particular. This may also translate into improved treatment and perhaps prevention of this common and intriguing viral infection.