Optimal vaccine efficacy requires not only a protective antigen, but also a strong immune activator as an adjuvant. Most viral vaccines, such as influenza vaccines and nonviral genetic vaccines (e.g., DNA vaccines), contain nucleic acids, which appear to act as essential 'built-in' adjuvants. Specific receptors, including Toll-like receptors, retinoic acid-inducible protein-I-like receptors, and nucleotide-binding oligomerization domain-like receptors can detect specific nucleic acid patterns, depending on the immunized tissue, cell type and intracellular localization. The resulting immune activation is uniquely regulated by intra- and intercellular signaling pathways, which are indispensable for the ensuing vaccine immunogenicity, such as antigen-specific T- and B-cell responses. Thus, elucidation and manipulation of immune signaling and interactions by nucleic acid adjuvants are essential for maximizing the immunogenicity and safety of viral and DNA vaccines.