Unmethylated CpG motifs in bacterial DNA and synthetic oligodeoxynucleotides activate immune cells that express Toll-like Receptor 9. Activation through this receptor triggers cellular signaling that leads to production of a proinflammatory and a Th1-type, antigen-specific immune response. The immunostimulatory effects of CpG oligodeoxynucleotides confer protection against infectious disease, allergy and cancer in animal models, and clinical trials have been initiated. However, CpG oligodeoxynucleotides may exacerbate disease in some situations. We will review current concepts in the mechanisms of activating Toll-like Receptor 9 with CpG oligodeoxynucleotides and highlight opportunities for using large animal models to better determine the mechanisms of action.