High-grade malignancies of the central nervous system continue to be refractory to multimodality therapy. Immunotherapy with monoclonal antibodies, biologic response modifiers (eg, interleukin-2), and autologous, activated lymphocytes offer the potential for more selective therapy. Current research is likely to help overcome obstacles inherent in current monoclonal antibody therapy, including cross-reactivity with normal tissues, impermeability of the blood-brain barrier, and immunogenicity of murine-derived monoclonal antibodies. Treatment with adoptive cellular therapy and biologic response modifiers has been limited by low killing activity and specificity of the activated lymphocytes, limited infiltration of implanted cells, and the toxicity associated with systemically administered biologic response modifiers. Improved specificity and killing efficacy of activated lymphocytes will allow integration of cellular immunotherapy into the treatment of central nervous system malignancies.