The natural immune response against HIV and other pathogens that cause chronic infection is insufficient for protection. Novel vaccine design and delivery strategies for optimization of HIV vaccines are urgently needed. These will require a better understanding of a number of factors including: the interplay between dendritic cells (DCs) and multiple cell types in linking innate signals that orchestrate subsequent adaptive immune responses; the regulation of DC function by viral and bacterial vectors, adjuvants and immunomodulatory molecules; and the temporal and synergistic relationships between C-type lectins, Toll-like receptors, NOD-like receptors and RIG-1-like receptors, chemokines and cytokines in enhancing immune responses. Here, we discuss current vaccine strategies for optimizing the induction of immune responses by the recruitment of DCs and the targeting of vaccine antigens to DCs.