Despite two centuries of vaccine use, only a few adjuvants and delivery systems are licensed for human use. This is partly because traditional vaccines based on attenuated live organisms already have them--their invasiveness provides efficient delivery to antigen-presenting cells and various naturally occurring components of the pathogens stimulate the innate immune system. But consideration of these immune potentiators and delivery systems has become important to the development of new subunit vaccines consisting of isolated antigens. Here we consider rational approaches to the discovery and development of immunostimulatory compounds and vaccine formulations that target innate immune responses.