Human herpesvirus 8 (HHV-8) is a gamma-2 herpesvirus, related genetically to simian herpesvirus saimiri (HVS), the prototype virus of this subgroup of the gammaherpesvirus subfamily. HHV-8 DNA is present in all forms of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), and in most forms of multicentric Castleman's disease (MCD), especially in HIV infected individuals. Of relevance to attempts to explain the molecular basis of HHV-8 associated neoplasia, are the unique genes specified by this virus, in particular angiogenic cytokines viral interleukin-6 (vIL-6) and viral CC-class chemokines (vCCL-1, vCCL-2, vCCL-3), mitogenic signaling membrane proteins variable ITAM-containing protein (VIP) and latency associated membrane protein (LAMP), pro-survival latently-expressed viral interferon regulatory factor (vIRF3), and the kaposin family of proteins that promote cell growth and cytokine production. Also of relevance are the angiogenic and cytokine-inducing viral G protein-coupled receptor (vGPCR), pro-proliferative and pro-survival latency proteins viral FLICE inhibitory protein (vFLIP) and latency-associated nuclear antigen (LANA), and G1-S phase cell-cycle promoter viral cyclin (v-cyclin), proteins specified also by other gamma-2 herpesviruses. The enormous progress on the characterization of the properties and biological activities of these proteins over the last ten years has provided insight into the potential mechanisms of HHV-8-induced neoplasia. Present data suggest that there operates a combination of cell transformation mediated by latently expressed proteins that promote cell proliferation and survival coupled with paracrine signaling functions mediated by either the viral cytokines or viral receptor-induced secreted cellular proteins. This review discusses the properties of the viral proteins believed to contribute to viral neoplasia via these mechanisms.