The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a G protein-coupled receptor (vGPCR) that has been implicated in the initiation of Kaposi's sarcoma, identifying vGPCR as an attractive target for preventing Kaposi's sarcoma. However, as only a fraction of cells in advanced Kaposi's sarcoma lesions express vGPCR, it is unclear whether this unique viral oncogene contributes to Kaposi's sarcoma progression. We therefore set out to determine whether the few cells that express vGPCR in established tumors represent an appropriate therapeutic target for the treatment of patients with preexisting Kaposi's sarcoma. To this end, we generated endothelial cell lines stably expressing vGPCR or key KSHV latently expressed proteins (vCyclin, vFlip, and LANA1). The endothelial cell line expressing vGPCR was rendered sensitive to treatment with the nucleoside analogue ganciclovir by using a bicistronic construct coexpressing the herpes simplex virus 1 thymidine kinase. S.c. injection into nude mice with mixed-cell populations formed tumors that approximate the ratio of vGPCR-expressing and KSHV latent gene-expressing cells. These mice were then treated with ganciclovir to specifically target only the vGPCR-expressing cells. Surprisingly, despite the expression of KSHV latent genes in the vast majority of tumor cells, specifically targeting only the few vGPCR-expressing cells in established tumors resulted in tumor regression. Moreover, we observed an increase in apoptosis of latent gene-expressing cells after the pharmacologic deletion of the vGPCR-expressing cells. These findings indicate that vGPCR may play a key role in Kaposi's sarcoma progression and provide experimental justification for developing molecular-based therapies specifically targeting vGPCR and its effectors for the treatment of Kaposi's sarcoma patients.