In 1994, the Kaposi's sarcoma‐associated herpesvirus (KSHV/HHV‐8) was identified as the etio¬logie agent of Kaposi's sarcoma (KS). KSHV has since been associated with two additional AIDS‐related ma¬lignancies: primary effusion lymphomas (PEL) and multicentric Castleman's disease (MCD). Although mo¬lecular characterization of the KSHV genome has re¬vealed several candidate oncogenes, infection with KSHV alone is not sufficient to cause KS, suggestive of an accomplice in KS initiation. Recent experimental evidence supports a key role for a particular KSHV gene, a constitutively‐active G‐protein‐coupled receptor (vGPCR), in the development of KS. However, it is unclear how a lytic gene expressed in cells destined to die can cause cancer. Here we propose that dysregulation of the viral gene program may lead to nonlytic vGPCR expression. Several candidate cofactors (e.g., HIV‐1 Tat, inflammation, aborted lytic cycle progres¬sion) are identified that may trigger vGPCR dysregulation, enabling oncogenic signaling pathways up‐regu¬lated by vGPCR, combined with the paracrine secretions from vGPCR‐expressing cells, to promote the initiation of KS. If KS is indeed dependent on vGPCR dysregulation, then the development of new therapeutic modalities specifically targeting this viral protein or its downstream targets may ultimately prove to be the most effective treatment strategy for this enigmatic disease.—Sodhi, A., Montaner, S., Gutkind, J. S. Does dysregulated expression of a deregulated viral GPCR trigger Kaposi's sarcomagenesis?