During sexual transmission of HIV, virus crosses mucosal epithelium and eventually reaches lymphoid tissue where it establishes a permanent infection. Evidence has accumulated that infection of Langerhans cells, which are resident dendritic cells in pluristratified epithelia, plays a crucial role in the early events of HIV transmission. HIV infection of Langerhans cells is regulated by surface expression of CD4 and CCR5. Thus, topical microbicides that interfere with HIV infection of Langerhans cells represent an attractive strategy for blocking sexual transmission of virus. Capture and uptake of HIV virions is another major pathway by which HIV interacts with dendritic cells. By contrast, this process is mediated by a newly described C-type lectin, DC-SIGN. It is well established that HIV-exposed dendritic cells transmit virus efficiently to cocultured T cells. Indeed, dendritic cell–T cell interaction, critical in the generation of immune responses, is a rich microenvironment for HIV replication both in vitro and in vivo. Dendritic cells that have captured virus via DC-SIGN, and not HIV-infected dendritic cells, probably facilitate most infection of T cells in chronically infected individuals. Therefore, blocking DC-SIGN-mediated capture of HIV represents a potential therapeutic antiviral strategy for HIV disease. Lastly, dendritic cells have been targeted both ex vivo and in vivo to initiate and enhance HIV-specific immunity. Although these approaches are promising for both therapeutic and prophylactic vaccines, much additional work is needed in order to optimize dendritic-cell-based immunization strategies.