The development of immunotherapeutic protocols for the treatment of human CNS neoplasia over the past two decades has been impressive. Several crucial aspects have been defined, characterized, and in many cases, optimized (Wikstrand CJ, Zalutsky MR, Bigner DD: In: Liau LM, Bigner DD (eds) Brain Tumor Immunotherapy. Humana Press (in press), 2000). Specific Mabs or constructs reacting with targetable antigens are currently available and in clinical trial. In addition, additional antigens currently under study (angiogenesis-related markers, developmentally associated antigens for medulloblastoma such as L1, and the identification of new targets by SAGE, just in its infancy, will provide a veritable library of available targets for therapy. The molecular engineering and affinity maturation techniques being applied to Mab fragment optimization have already been rapidly effective in generating a variety of Mab constructs of appropriate affinity for clinical trial; as new targets are defined, and experience is accrued with the various constructs currently and prospectively available, the optimal targeting of a multitude of antigens will be possible.