Kaposi's sarcoma (KS) is an angioproliferative disease caused by infection with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV). This virus encodes 84 open-reading frames (ORFs), many of which represent pirated versions of human genes. One of them, ORF74, encodes a predicted seven-span transmembrane receptor termed vGPCR that is similar to the human IL8 receptor CXCR2, which displays strong oncogenic activity in vitro and in vivo by a complex interplay of direct and autocrine/paracrine mechanisms. vGPCR has been shown to be both necessary and sufficient for the formation and progression of KS-like lesions in experimental model systems. Due to the fundamental role of vGPCR in the pathogenesis of KS, understanding the molecular mechanisms elicited by this unique chemokine receptor can be exploited to devise new strategies for KS management, as well as to gain novel insights into how KSHV subverts key physiological processes such as cell proliferation, chemotaxis, angiogenesis, and immunomodulation for its replicative advantage. Here we describe multiple techniques and strategies that have been used to study the unique properties and functions of vGPCR and its role in oncogenesis.