HIV infection is likely to remain a significant medical and scientific problem well into the twenty-first century. During the first 15 years of the epidemic, much has been learned about the biology of HIV infection, but the majority of biomedical research has focused on the peripheral circulation. It is likely that the behavior of the virus within the unique immunologic environment of the intestinal mucosa differs from that which is observed in the periphery. Many clinical and epidemiologic features of HIV infection offer compelling reasons to encourage further examination of the mucosal immune system's role in AIDS pathogenesis. This article has touched on most of the significant observations concerning the mucosal immune system and HIV infection, and it is clear that much remains to be done. As mentioned earlier, the mucosal abnormalities observed in HIV infection are likely to have many causes. Careful evaluation of patients with early disease and fewer confounding variables may provide fresh insight into AIDS pathogenesis. Similarly, prospective evaluation of selected patient populations may be more informative in characterizing the progressive alterations in mucosal immune function than random cross-sectional studies of poorly defined groups. It is equally important for immunologic assessment to be correlated with nutritional and symptomatic evaluation. Finally, the success or failure of future antiretroviral therapies will be critically related to the impact of such agents on lymphoid reservoirs of HIV infection such as the gastrointestinal tract, which are at present refractory to treatment.