Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8), which is a virus that appears to be etiologic for Kaposi's sarcoma, primary effusion lymphomas, and multicentric Casllcman 's disease in humans, encodes a G protein-coupled receptor (ORF 74. KSHV GPCR) that is homologous to human chemokine receptors. KSHV GPCR is more promiscuous than most chemokine receptors in that it binds CC and CXC chemokines. For GPCRs encoded within viral genomes. KSHV GPCR is novel in that it exhibits constitutive signaling activity. It signals via the phospholipase C-inositol 1.4.5-tri-sphosphate-1.2-diacylglycerol pathway and activates the Jun kinase/SAP kinase and p38 MAP kinase pathways. Expression of KSHV GPCR in rat NRK fibroblasts stimulates cell proliferation. KSHV GPCR can transform mouse NIH 3T3 fibroblasts in vitro and KSHV GPCR-expressing NIH 3T3 cells form tumors in mice. Thus. KSHV GPCR displays activities of human oncogenes. Moreover. KSHV GPCR induces expression of vascular endothelial growth factor (VEGF). a potent and efficacious stimulator of angiogenesis, in NIH 3T3 cells. Thus, because of its tumorigenic and angiogenic potential. KSHV GPCR is likely to play a role in the pathogenesis of diseases associated with KSHV infection.