Kaposi sarcoma (KS) is the most common tumor arising in HIV-infected patients and is an AIDS-defining illness by the Centers for Disease Control guidelines. The clinical course of AIDS-related KS is highly variable, ranging from minimal stable disease to explosive growth. Recent advances in the elucidation of the pathogenesis of KS are uncovering many potential targets for KS therapies. Such targets include the processes of angiogenesis and cellular differentiation, sex hormones, and the KS herpesvirus/human herpesvirus-8. With the increasing recognition that effective antiretroviral regimens are associated with both a decreased proportion of new AIDS-defining KS cases and a regression in the size of existing KS lesions, most, if not all, KS patients should be advised to take antiretroviral drugs that will maximally decrease HIV-1 viral load. Five agents are currently approved by the Food and Drug Administration for the treatment of KS: alitretinoin gel for topical administration; and liposomal daunorubicin, liposomal doxorubicin, paclitaxel, and interferon-alpha for systemic administration. Many more agents, particularly angiogenesis inhibitors, are in early clinical development. The potential interaction between anti-KS agents and antiretroviral agents needs to be kept in mind. Virtually all patients with KS can derive benefit from the many approved and investigational agents developed through years of collaborative translational and clinical research.