AIDS-related Kaposi's sarcoma (KS) is a neoplasm that results from the co-infection of HIV and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8). Targeting HIV with highly active antiretroviral therapy has attenuated the natural history of this disease. Recent discoveries have elucidated the role of multiple signaling pathways in the pathogenesis of AIDS-related KS. In particular, KSHV/HHV8-specific gene products, including a G-protein-coupled receptor (vGPCR) and a homolog of human IL-6 (vIL-6), have been implicated in the development of tumorigenesis and angiogenesis. In addition, KSHV/HHV8 can modulate cellular growth and angiogenic pathways to augment malignant transformation and potentiate growth. This article discusses the main signaling pathways that are implicated in the pathogenesis of AIDS-related KS, reviews recently completed clinical trials and anticipates the future direction of molecularly targeted agents in this disease.