The most recently identified human herpesvirus, Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8), has been found to be a necessary, although perhaps not sufficient, etiologic agent for all forms of KS (1, 2). This virus is also invariably present in a rare subset of malignant lymphomas, primary effusion lymphomas (PELs), and in a significant percentage of patients with multicentric Castleman’s disease, an angiolymphoproliferative disorder (3, 4). Both KS and PEL occur more frequently, but not exclusively, in HIV-infected individuals, and all cases of HIV-related multicentric Castleman’s disease are infected with KSHV. These findings suggest an important role of immunosuppression and HIV infection in KSHV-mediated pathogenesis. Although it remains controversial whether KS is a malignant neoplasm, KS lesions probably evolve from a reactive, inflammatory/angioproliferative process into true clonal cancers. Thus, KS is generally considered a malignancy, especially because of its frequent multifocal and aggressive behavior. Given the definitive association of KSHV with two different human malignancies, it is not difficult to consider KSHV to be a human oncogenic virus. KSHV is a gammaherpesvirus that is homologous to EBV and herpesvirus saimiri (HVS), human and simian viruses, respectively, that are able to transform lymphoid cells in culture and cause malignant lymphomas in some circumstances. Genomic sequencing has revealed that KSHV contains several genes with likely oncogenesis-related functions that subvert pathways involved in cellular activation, proliferation, differentiation, and survival. Many of these genes are viral homologues of cellular genes, including those encoding viral cyclin D, IFN regulatory factors (IRFs), viral IL-6 (vIL-6), BCL-2, FLICE-inhibitory protein (FLIP), three chemokines (viral macrophage inflammatory protein [vMIP]-I,-II, and-III) and last, but not least, a G protein–coupled receptor (KSHV GPCR). Three of these genes have been found to be transforming in mouse fibroblast assays (vIRF, KSHV GPCR, and vIL-6), and two are homologous to cellular oncogenes (vBCL-2 and v-cyclin D). Two additional viral genes having no direct cellular counterpart, those encoded by open reading frame K1 (containing an immunoreceptor tyrosine-based activation motif [ITAM]) and K12, have also been found to be transforming in certain experimental assays. Therefore, KSHV qualifies as the virus with the most putative oncogenes identified to date. Thus, the following dilemma: why are KSHV-associated neoplasms so rare in the general population in spite of a seroprevalence of KSHV infections of at least 5% in Western countries? Why is KSHV only poorly transforming after infecting cells in culture? This may be partially explained by the concept that KSHV-mediated pathogenesis will be determined by the specific pattern of viral gene expression and the specific cellular background in which these genes are expressed, both of which are highly dependent on host factors (5, 6). Most of the genes found or suspected to be transforming are lytic genes, which are only transcribed in a subset of cells in KS lesions and PEL. However, the pathogenic potential of a single gene product thus sparsely expressed is elegantly demonstrated in the article by Yang et al. in this issue (7). The report by Yang et al. provides the first transgenic mouse model for KS using a single KSHV gene, the chemokine receptor KSHV GPCR. In this study, it was found that expression of KSHV GPCR in hematopoietic cells of transgenic mice leads to angioproliferative lesions that exhibit most of the characteristics of KS. This viral …