Synthetic oligodeoxynucleotides containing CG motifs (CpG ODN) have potent immunostimulatory properties, and have potential as immunotherapeutic agents in cancer. Animal models suggest CpG ODN can activate a variety of immune effector cells such as natural killer (NK) cells, and also enhance the efficacy of tumor immunization when used as immune adjuvants or to directly activate antigen-presenting cells. CpG ODN are also capable of altering the expression of a number of antigens by malignant B-cells, including those targeted by monoclonal antibodies (moAbs) and those involved in communication with T cells. The ability of CpG ODN to activate the immune effector cells that participate in antibody-dependent cellular cytotoxicity (ADCC), upregulate target antigen, and perhaps induce development of an active immune response, suggest these agents may be capable of enhancing the efficacy of antitumor moAb therapy. Such enhanced efficacy has been demonstrated in animal models and is now undergoing evaluation in clinical trials.