A dendritic cell (DC) encountering an immunodeficiency virus should pose a threat to the virus, by efficiently processing and presenting viral antigenic determinants to activate specific anti-viral T and B cell immunity. While this may occur in vivo, it is apparent that DC-entrapped viruses can freely spread between cells, move to distal tissues, and proliferate rapidly particularly upon meeting CD4 + T cells. In fact, the latter is further augmented when the T cells are activated. Thus, it seems that immunodeficiency viruses exploit the unique ability of DCs to survey the periphery and capture incoming pathogens, traffic around the body often targeting the lymphoid tissues, and efficiently communicate with naïve and memory T cells. Combined with the fact that DCs are likely the first leukocytes interacting with virions crossing the mucosae, these features provide the basis on which the virus maximizes its chance to establish infection even in the face of immune activation. How this is actually achieved by the virus is still an enigma. Herein, we intend to summarize what is known about how distinct DC subsets and immunodeficiency viruses interact, what cellular and viral factors influence these events, and how this drives virus replication versus stimulation of protective immunity. Clarifying these issues is necessary to define the exact role of DCs in the transmission and dissemination of HIV infection, to facilitate the development of methods to improve the immune-activating capacity of DCs as well as the design of strategies to prevent DC-driven infection.