The gastrointestinal tract plays a fundamental role in the pathogenesis of HIV-1 disease. Virologic and immunologic events within the mucosa affect the progression of HIV-1 disease at virtually all stages of the infection. The mucosal surface of the gastrointestinal tract is the major route by which HIV-1, the causative agent of AIDS, enters the host in homosexuals and infants. The mucosa may participate in the initial selection of HIV-1 isolates that are inoculated onto the mucosal surface, and as the largest lymphoid organ in the body, the mucosa is a potential reservoir for HIV-1-infected cells. The presence of mucosal microorganisms (or their products) and the increased tissue levels of cytokines provide a rich source of local factors capable of activating mononuclear cells for increased HIV-1 expression. Local and systemic immunosuppression predisposes the gastrointestinal tract mucosa to a complex and diverse array of opportunistic pathogens. Despite the importance of the gastrointestinal tract in HIV-1 disease, advances in elucidating the role of the mucosa in the pathogenesis of HIV-1 infection have lagged far behind advances in defining the role of the systemic immune system, owing in large part to the technical difficulties associated with the isolation, purification, and culture of mucosal cells. This review highlights recent studies that provide insight into the role of the gastrointestinal tract in the pathogenesis of HIV-1 disease.