The Kaposi's sarcoma herpesvirus (KSHV) has been identified as the etiologic agent of Kaposi's sarcoma (KS), but initial events leading to KS development remain unclear. Characterization of the KSHV genome reveals the presence of numerous potential oncogenes. To address their contribution to the initiation of the endothelial cell-derived KS tumor, we developed a novel transgenic mouse that enabled endothelial cell-specific infection in vivo using virus expressing candidate KSHV oncogenes. Here we show that transduction of one gene, vGPCR, was sufficient to induce angioproliferative tumors that strikingly resembled human KS. Endothelial cells expressing vGPCR were further able to promote tumor formation by cells expressing KSHV latent genes, suggestive of a cooperative role among viral genes in the promotion of Kaposi's sarcomagenesis.