Neuroblastoma is the most common extracranial solid tumor malignancy of childhood. Although it is generally responsive to treatment, high risk cases of neuroblastoma frequently recur. The prognosis for relapsed cases is extremely poor despite aggressive therapy. The frequency of relapse and subsequent failure of further treatment has spurred the need to develop non toxic and more effective treatments for targeting residual tumor cells during the phase of minimal residual disease. Traditional cancer therapies are non-specific, leading to the destruction of normal, healthy tissues. Failure to induce specific tumor immunity may be due to several immunosuppressive factors. Primary amongst these factors are: lack of co-stimulatory molecules on the surface of tumor cells, the ability of the tumor to modulate immunity in a suppressive manner and the presence of an immunosuppressive microenvironment at the location of the tumor. Unfortunately, tumor tolerance impedes the ability to establish immunity to tumor antigens and overcoming this tolerance is essential to developing effective tumor immunity. Vaccine strategies that target host immune effector cells with synthetic oligodeoxynucleotides (ODNs) that contain unmethylated CpG motifs (CpG-ODNs) represent a novel approach to overcoming tolerance in cancer therapy. This approach enables biasing of host immunity toward a proinflammatory Th1 and thus anti-tumor response. The addition of immunogenic tumor specific antigen to the CpG-ODN vaccine may allow for specific targeting and killing of established tumors.