Bacterial DNA contains immunostimulatory CpG motifs that interact with toll-like receptor 9 on immune cells to stimulate the production of cytokines, chemokines and immunoglobulins. Synthetic oligodeoxynucleotides (ODNs) containing CpG motifs mimic the activity of bacterial DNA. Recently, several structurally distinct types of CpG ODN were identified that differentially activate human immune cells. These ODNs may be useful as vaccine adjuvants, anti-allergens and in the treatment of infectious diseases and cancer. Yet CpG-driven immune activation can have deleterious consequences, such as increasing the host's susceptibility to autoimmune disease. The immunomodulatory activity of CpG DNA can be blocked by DNA containing G-rich 'suppressive' motifs. The therapeutic potential of these immunostimulatory and immunosuppressive ODNs are discussed in this review.