Before the first clinical descriptions of the acquired immunodeficiency syndrome (AIDS), Kaposi’s sarcoma (KS) was a rare tumor among Western populations, occurring in only 0.02% to 0.06% per 100,000 people.1 In a typical dermatology practice, it was unusual for a busy practitioner to see more than one such case every 5 years. By June and July of 1981, however, reports from California and New York described large numbers of homosexual men who were afflicted with pigmented skin lesions of KS, either as an initial manifestation of a compromised immune system or following opportunistic infections such as oral candidiasis and Pneumocystis carinii pneumonia.2‐ 4 Since then, approximately 15% to 25% of men infected with human immunodeficiency virus (HIV) in the United States have been diagnosed with KS.5 Typically, these tumors involve skin and lymph nodes and, less frequently, visceral organs. Although visceral KS can cause life-threatening symptoms, it is usually the dermatologic manifestations that lead patients to their physician’s office. The characteristic, unsightly cutaneous lesions of AIDS-related KS severely compromise physical appearance and often lead to social stigmatization. In response to these concerns and because of the diverse clinical presentations of KS, physicians must individualize treatment approaches, taking into account the patient’s overall clinical condition, immune status, psychological status, and other concurrent medical problems and therapies. The natural history of AIDS-related KS has changed with the widespread use of highly active antiretroviral therapy (HAART). Recent declines in morbidity and mortality due to AIDS have been attributed to the use of these three-drug or four-drug combination antiretroviral regimens, which generally include nucleoside analog reverse transcriptase inhibitors and either protease inhibitors or nonnucleoside reverse transcriptase inhibitors. As patients with HIV and KS live longer due to the beneficial effects of HAART, a renewed interest in the development of therapies that are not only safe, efficacious, and convenient but also minimize the risk of drug interactions and toxicities takes on greater importance.6 This article will briefly review the changing epidemiology of KS in the HAART era and discuss the pathology and pathogenesis of KS. Recent advances in the treatment of HIV-associated KS, including the potential to modulate the natural history of this tumor with HAART, will also be discussed in conjunction with newer and more specific targeted therapies.