Successful vaccines contain an adjuvant component that activates the innate immune system, thereby eliciting antigen-specific immune responses. Many adjuvants appear to be ligands for toll-like receptors (TLR), which are thus promising targets for the development of novel adjuvants to elicit vaccine immunogenicity. However, recent evidence suggests that some adjuvants activate the innate immune system in a TLR-independent manner possibly through other pattern recognition receptors and signaling machinery. In particular, newly identified intracellular retinoic-acid-inducible gene (RIG)-like receptors, NOD-like receptors, or even as yet unknown recognition machinery for the adjuvant may regulate TLR-independent vaccine immunogenicity. To develop optimal vaccines, it will be critical to understand how TLR-dependent and TLR-independent innate immune activation, by various adjuvants, control the consequent adaptive immune responses to vaccine.