Biological efforts to prevent HIV infection center on four independent approaches: inducing adaptive immune responses through vaccination, augmenting innate responses, using peri-exposure prophylactic drug therapy, and developing microbicides and/or recombinant antiviral microbial products. While all four of these approaches have promise, they still require significant optimization and further clinical trials. Indeed, successful prevention of HIV infection will likely require a combination of these approaches. Such development efforts require a better understanding of viral and immunological events at the site of transmission. This Keystone Symposia meeting will have a focus on mucosal immunology as well as the interplay between the virus and innate and adaptive immune responses, particularly during the acute phase of the infection. Leading experts in the fields will discuss recent scientific advances in these varied approaches to preventing infection and present data from recent clinical trials testing their efficacy.