Kaposi sarcoma (KS) is a multicentric angioproliferative disorder characterized by spindle cell proliferation, neo-angiogenesis, inflammation, and edema. Human herpesvirus (HHV)-8, a gamma-herpesvirus, is a critical factor, but is not alone sufficient for the initiation of KS. Other cofactors such as human immunodeficiency virus (HIV), host-derived cytokines, chemokines, and growth factors are required for the development of KS. Whether HIV-associated KS is a reactive hyperplastic inflammatory lesion or a true neoplasm is still controversial. It is likely that HIV-associated KS begins as a reactive disorder that in some cases progresses to a monoclonal, an oligoclonal, and a polyclonal neoplasm.