The search for the etiologic agent for Kaposi sarcoma led to the discovery of Kaposi sarcoma-associated herpesvirus (KSHV) in 1994. KSHV, also called human herpesvirus-8, has since been shown to be the etiologic agent for several other tumors and diseases, including primary effusion lymphoma (PEL), an extracavitary variant of PEL, KSHV-associated diffuse large B-cell lymphoma, a form of multicentric Castleman disease, and KSHV inflammatory cytokine syndrome. KSHV encodes several genes that interfere with innate and specific immunity, thwart apoptosis, enhance cell proliferation and cytokine production, and promote angiogenesis, and these play important roles in disease pathogenesis. HIV is an important cofactor in Kaposi sarcoma pathogenesis, and widespread use of antiretroviral therapy has reduced Kaposi sarcoma incidence. However, Kaposi sarcoma remains the second most frequent tumor arising in HIV-infected patients in the United States and is particularly common in sub-Saharan Africa. KSHV prevalence varies substantially in different populations. KSHV is secreted in saliva, and public health measures to reduce its spread may help reduce the incidence of KSHV-associated diseases. Although there have been advances in the treatment of Kaposi sarcoma, KSHV–multicentric Castleman disease, and PEL, improved therapies are needed, especially those that are appropriate for Kaposi sarcoma in resource-poor regions.