Twenty years after its discovery [1], Kaposi’s sarcoma herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) continues to be an enigmatic oncovirus, while AIDS-associated Kaposi’s sarcoma (AIDS-KS) remains a clinical challenge in endemic regions in Africa and for some patients receiving anti-retroviral therapy (ART)[2–4]. KSHV, a gamma-2 herpesvirus, is the etiological agent of Kaposi’s sarcoma (KS)[2, 3]:(1) KSHV is strictly associated with all clinical forms of the disease, including classic KS affecting elderly individuals of Mediterranean or Ashkenazi origin, transplant-associated KS, endemic KS affecting sub-Saharan countries, and AIDS-associated or epidemic KS.(2) KSHV is found in KS spindle cells.(3) KSHV infection precedes the onset of KS.(4) KSHV seroprevalence is higher in areas of high KS incidence.(5) KSHV encodes many viral oncogenes.(6) KSHV transforms and induces tumorigenesis in endothelial cell lineage [3, 5, 6]. Like other human oncogenic viruses [7], KSHV infection alone is generally not sufficient to cause KSHV-associated cancers, which also include two B-cell lymphoproliferative disorders associated with HIV/AIDS: Multicentric Castlemans Disease and Primary Effussion Lymphoma [8]. This indicates that other co-factors are necessary for malignant transformation [2, 7]. KSHV seroprevalence in the general population ranges from less than 10% in the United States and Northern Europe to 30%–50% in endemic areas, where KS lifetime-incidence could be as high as 1%[9]. KS incidence increases dramatically in HIV-infected individuals, indicating that HIV/AIDS is a potent co-factor for KSHV oncogenesis [2–4, 9]. Yet, even in this high-risk group, the majority of KSHV-infected individuals will not develop KS, indicating that complex interactions between KSHV, genetic susceptibility, immune status, and HIV infection determine the oncogenic outcome of KSHV infection.