Unlike mammalian DNA, bacterial, plasmid, and synthetic DNA containing unmethylated CpG dinucleotides in specific sequence contexts are recognized by the Toll-like receptor 9 expressed by B cells and plasmacytoid dendritic cells, and trigger the activation of the innate and adaptive immune system. Upon signaling, CpG DNA induces B cells, natural killer cells, macrophages, and dendritic cells to proliferate, differentiate, take up, and present antigen and secrete a variety of immunoglobulins, chemokines, and predominantly Th1-type cytokines. Preclinical studies in mice and primates show that DNA sequences containing CpG motifs can selectively promote cellular and/or humoral immune responses in vivo. Early results from ongoing clinical studies indicate that CpG oligonucleotides (ODN) are well tolerated and improve the immune response to microbial vaccines. This work examines the progress in utilizing CpG ODN as adjuvants in conventional and DNA vaccines.