The genomes of bacterial and viral DNA contain a much higher frequency of unmethylated CpG dinucleotides than those of vertebrates. This difference in genome structure allows the innate immune system of vertebrates to distinguish bacterial or viral DNA from self-DNA, and consequently to perceive a ‘danger signal’ when bacterial or viral DNA is encountered. Multiple sources of evidence suggest that CpG motifs, including bacterial DNA and CpG ODNs (synthetic oligodeoxynucleotides containing unmethylated CpG), are capable of evoking a range of immunostimulatory effects in vertebrates and have a tremendous potential to be used as therapeutic agents and adjuvants. CpG motifs with different sequences have been shown to induce various types or levels of immunostimulatory responses whereas the immunostimulatory effects of CpG motifs are species-specific. A better understanding of CpG recognition at the molecular level is fundamental to the identification of those motifs that have desired immunostimulatory responses. It is hoped that this would allow the optimization and application of CpG motifs as therapeutic agents and adjuvants, for numerous diseases in various species.