It has become evident that the gastrointestinal tract is preferentially and profoundly depleted of CD4+ T cells during acute HIV-1 infection. The enhanced susceptibility of gastrointestinal lymphoid tissue to HIV-1 is in part due to the large complement of CCR5+ memory CD4+ T cells resident at this site. Here we summarize the recent findings demonstrating that the gastrointestinal tract plays a critical role in the pathogenesis of acute HIV-1 and simian immunodeficiency virus infections. Ongoing work in this field is likely to have a significant effect on HIV research in the near future.