Human immunodeficiency virus (HIV) pathogenesis has proven to be quite complex and dynamic with most of the critical events (e.g., transmission, CD4(+) T-cell destruction) occurring in mucosal tissues. In addition, although the resulting disease can progress over years, it is clear that many critical events happen within the first few weeks of infection when most patients are unaware that they are infected. These events occur predominantly in tissues other than the peripheral blood, particularly the gastrointestinal tract, where massive depletion of CD4(+) T cells occurs long before adverse consequences of HIV infection are otherwise apparent. Profound insights into these early events have been gained through the use of nonhuman primate models, which offer the opportunity to examine the early stages of infection with the simian immunodeficiency virus (SIV), a close relative of HIV that induces an indistinguishable clinical picture from AIDS in Asian primate species, but importantly, fails to cause disease in its natural African hosts, such as sooty mangabeys and African green monkeys. This article draws from data derived from both human and nonhuman primate studies.