Recent progress in HIV-1 and SIV pathogenesis has revealed that mucosal tissues, primarily the gastrointestinal tract, are major sites for early viral replication and CD4+ T-cell destruction, and may be the major viral reservoir, even in patients receiving HAART. This is likely attributable to the fact that the majority of mucosal CD4+ T-cells co-expressing chemokine receptors requited for HIV-1 entry, reside in mucosal tissues. Furthermore, the intestinal mucosal immune system is continuously bombarded by dietary antigens, resulting in continual lymphocyte activation, dissemination, and homing of these activated lymphocytes (including CCR5+CD4+ T-cells) throughout mucosal tissues. Thus, the intestinal immune system represents a very large target for HIV-infection, which is continually generating newly activated CD4+ T-cells that are the preferred target of infection. Thus, HIV-1 appears uniquely adapted to persist and thrive in the mucosal-tissue environment. The selective loss of intestinal CD4+ T-cells from immune-effector sites is also likely to explain, at least in part, the preponderance of opportunistic infections at mucosal sites. It is increasingly evident that effective therapies and vaccines must be directed towards eliminating HIV-1 in mucosal tissue reservoirs, protecting mucosal CD4+ T-cells and stimulating effective mucosal immune responses.