Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphomas represent a significant and formidable clinical problem. They also represent an important biologic model for investigating the development and progression of high-grade malignant lymphomas and for studying lymphomas that develop in the setting of immune deficiency. A vast majority of non-Hodgkin's lymphomas exhibit clonal immunoglobulin gene rearrangements and, hence, are B-cell neoplasms. Most express B-cell phenotypes, but a minority, predominantly body cavity-based tumors, express indeterminate phenotypes. AIDS-associated non-Hodgkin's lymphomas do not contain HIV. However, approximately 40% of systemic non-Hodgkin's lymphomas, predominantly those with immunoblastic plasmacytoid morphology, and essentially 100% of primary central nervous system AIDS-associated non-Hodgkin's lymphomas contain Epstein-Barr virus. The c-myc protooncogene is rearranged in approximately 80% of systemic cases, predominantly in those with Burkitt's and Burkitt's-like morphology. Point mutations of the ras gene are detectable in approximately 15% of systemic cases. The p53 tumor-suppressor gene is mutated in approximately two thirds of systemic AIDS-associated Burkitt's and Burkitt's-like non-Hodgkin's lymphomas. The retinoblastoma tumor-suppressor gene does not appear to be mutated or deleted in AIDS-associated non-Hodgkin's lymphomas. In summary, various genetic lesions occur in AIDS-associated non-Hodgkin's lymphomas, which appear to vary according to the anatomic site of disease (systemic vs central nervous system vs body cavity) and the histopathology (Burkitt's vs immunoblastic vs large cell). Further active investigation is necessary to determine the role of these and possibly other genetic lesions in AIDS lymphomagenesis.