Kaposi’s sarcoma (KS) may be considered as a model of both malignancy and chronic inflammation. In Highly Active Antiretroviral Therapy (HAART) era KS remains the second most frequent tumor in HIV-infected patients worldwide and occurs in over 50% of cases with advanced HIV infection. Its development depends upon infection with a γ-herpesvirus from the Rhadinovirus genus called KS-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV8). Almost 50% of individuals acquiring KSHV infection with pre-existing HIV infection develop KS. This observation suggests that an already damaged immune system may predispose to a higher KSHV load, with subsequent KS development. Considering the elevated prevalence of KSHV in men having sex with men (MSM), it was suggested that it could be transmitted sexually. KSHV transmission by blood transfusion is documented, although rare. KS lesions are comprised of both distinctive spindle cells of endothelial origin and a variable inflammatory infiltrate, which suggests that KS may result from reactive hyperproliferation induced by chronic inflammation, and therefore it is not a true neoplasm. KS has a variable clinical course ranging from very indolent forms to a rapidly progressive disease. Treatment decisions must take into consideration the extent and the rate of tumor growth, patient’s symptom, immune system conditions and concurrent HIV-related complications. HAART represents the first treatment step for slowly progressive disease. HAART with concomitant chemotherapy is indicated for visceral disease and/or rapidly progressive disease, and maintenance (M)-HAART after systemic chemotherapy may be effective as anti-KS therapy after debulking CT. Systemic CT is reserved for patients who do not respond to HAART and/or have widespread, symptomatic, rapidly progressive, life-threatening disease with visceral involvement and an IRIS-associated flare. The angiogenic nature of KS makes it particularly suitable for therapies based on targeted agents such as angiogenesis inhibitors and tyrosine kinase inhibitors. The aim of this article is to provide an up-to-date review of the current status and perspectives of AIDS-related KS in the HAART era.