CpG is a higher frequency of unmethylated deoxycytidyl-deoxyguanosine dinucleotides in bacterial genome. Small oligodeoxynucleotides (ODN) with unmethylated CpG (CpG ODN) are able to perfectly mimic the immunostimulatory activity of bDNA. CpG ODNs bind to and trigger cells that express Toll-like receptor 9 (TLR9), booting an innate immune response that supports the subsequent development of adaptive immunity. Researches demonstrate that TLR9 agonists improve antigen presentation and the induction of vaccine-specific cellular and humoral responses. More than 100 clinical trials utilizing CpG ODNs have been conducted that evaluated their utility in preventing or treating allergy, infectious diseases, and cancer.