This chapter reviews the immunobiology of mucosal HIV-1 infection, emphasizing the key differences in virus-host cell interaction in the mucosal and systemic immune systems. The mucosal surfaces of the genital and gastrointestinal tracts are the route by which HIV-1 enters the host in virtually all heterosexual, homosexual, and vertical transmissions. The efficiency of HIV-1 transmission across the mucosa is a function of both donor infectiousness and recipient susceptibility. After crossing the mucosal surface or possibly within the mucosa, HIV-1 may first encounter myeloid-derived dendritic cells (DCs). These cells likely deliver virus to the ultimate target cells, CD4+lymphocytes and macrophages. Mucosal trauma during heterosexual and homosexual contact may disrupt the epithelial barrier and provide HIV-1 direct access to the microcirculation of the mucosa. In the absence of highly active antiretroviral therapy (HAART), HIV-1 infection in human gastrointestinal mucosa is associated with a profound decline in the number of lamina propria CD4+ lymphocytes. HIV-1 infection of monocyte-derived macrophages in culture and potentially in vivo-follows a proscribed pattern in which the virus initiates signal transduction events, leading to transient transcription of genes associated with the host defense and/or viral compatibility. © 2005 Elsevier Inc. All rights reserved.