The immune system is ignorant or even unresponsive to most foreign proteins that are injected in a soluble, deaggregated form, but when injected together with an immune-stimulating agent (i.e. an adjuvant, such as CpG-rich DNA), these foreign proteins can generate robust immunity and long-lived memory to the antigen. In fact, the nature of the adjuvant is what determines the particular type of immune response that follows, which may be biased towards cytotoxic T-cell responses, antibody responses, particular classes of T-helper responses, or antibody isotypes. Clearly, the ability of a vaccine to skew the response toward a particular type is of paramount importance, because different pathogens require distinct types of protective immunities. Therefore, the quest to manipulate the immune system to generate optimally effective immunity against different pathogens can justifiably be considered the 'grand challenge' of modern immunology. Central to this issue is a rare but widely distributed network of cells known as dendritic cells (DCs). DCs, which have been called 'Nature's adjuvants,' express pathogen recognition receptors, such as the Toll-like receptors (TLRs) and C-type lectins, which enable them to sense and respond to microbes or vaccines. Research in the last decade has demonstrated a fundamental role for DCs in initiating and controlling the quality and strength of the immune response. As such, DCs and TLRs represent attractive immune modulatory targets for vaccinologists. The present review provides a summary of emerging themes in the biology DCs and TLRs, with a particular focus on relevance for vaccine development.