Any immunotherapeutic approach to cancer cell eradication is based upon the specific recognition of neoplastic cells and the sparing of surrounding normal tissue; perhaps nowhere is this distinction more important than within the central nervous system, due to the diffuse infiltrative nature of primary glial tumor cell growth. Whether ultimate effect moieties are immunoglobulins, fragments and/or their constructs with drugs, toxins, radionuclides, or immune cells, the specificity of effector: cell surface marker is crucial. This review describes the identification, immunologic characterization, and biologic behavior of a transmembrane tumor-specific altered growth factor receptor molecule which may well serve as a mediator of multiple immunotherapeutic approaches: the class III variant of the epidermal growth factor receptor, EGFRvIII.