Central nervous system loco-regional disease relapse is a common etiology of treatment failure for medulloblastoma (MB)/primitive neuroectodermal tumors. Therapeutic targeting of primary disease and the adjacent craniospinal cerebral spinal fluid pathways should decrease relapse rates and allow for the curtailed use of radiation therapy. The adoptive transfer of tumor-specific cytolytic T cells (CTLs) to the tumor bed and cerebral spinal fluid is an attractive strategy, but limited in its clinical application owing to the paucity of defined antigens consistently expressed by these tumors and their potential to escape T-cell recognition by expressing low level surface human leukocyte antigen. Here, we describe the human leukocyte antigen-independent recognition of MB cell-surface IL13Ralpha2 by genetically modified CTLs expressing an IL13-zetakine chimeric immunoreceptor. We found that IL13-zetakine+ CTLs exhibit potent cytolytic activity toward IL13Ralpha2 Daoy cells, and are activated to secrete proinflammatory cytokines such as interferon-gamma. By employing an orthotopic NOD-scid murine model in which intraventricularly seeded Daoy cells form tumors on leptomeningeal surfaces, regression of established ffLuc+ Daoy xenografts in response to intraventricularly delivered IL13-zetakine+ CD8+ CTLs was observed using biophotonic imaging. These studies support the rationale for exploring the clinical utility of targeted immunotherapy using adoptively transferred IL13-zetakine redirected CTLs as a therapeutic component for treating IL13Ralpha2+ MB/primitive neuroectodermal tumors.