Although human herpesvirus 8 (HHV-8) is the etiologic agent of Kaposi sarcoma (KS), there are no formal guidelines for the clinical management of HHV-8 infection. In patients infected with human immunodeficiency virus (HIV), highly active antiretroviral therapy (HAART) is the best tool for the prevention of KS. In patients who have undergone transplantation, KS is often managed by curtailing immunosuppressive therapies, despite the potential adverse consequences for graft survival. Interventions related to HHV-8 infection might improve the management of KS in immunocompromised patients. However, knowledge from HHV-8 research cannot yet be translated into clinically useful interventions. Achieving clinical utility will require the commercial development of diagnostic tools currently available only in research settings and the evaluation of potential interventions. Such interventions might include the use of HHV-8 diagnostics to identify patients at high risk and to aid in the early detection of KS, prophylaxis with antiherpes drugs to prevent KS, treatment of KS with antiherpes drugs, and donor/recipient screening for organ transplantation.