The molecular pathogenesis of systemic acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHL) is a complex process involving both host factors and the accumulation of genetic lesions within the tumor clone. On the basis of the pattern of molecular lesions involved in these tumors, several distinct pathogenetic pathways can be presently identified in AIDS-related lymphomagenesis. These pathways selectively associate with the different clinicopathologic variants of AIDS-NHL. AIDS-related Burkitt's lymphoma is characterized by activation of c-MYC in all cases, disruption of p53 in 60% of the cases, and infection by Epstein-Barr virus (EBV) in 30% of the cases. AIDS-related diffuse large-cell lymphoma harbor frequent EBV infection (80%) and, in 20% of the cases, BCL-6 rearrangements. Finally, the pathogenesis of AIDS-related body cavity-based lymphoma involves infection by human herpesvirus-8 in all cases and frequently also the co-infection by EBV.