Almost all individuals diagnosed with glioblastoma multiforme (GBM) will die of their disease as no effective therapies exist. Clearly, novel approaches to this problem are needed. Unlike the adaptive αβ T cell-mediated immune response, which requires antigen processing and MHC-restricted peptide display by antigen-presenting cells, γδ T cells can broadly recognize and immediately respond to a variety of MHC-like stress-induced self antigens, many of which are expressed on human GBM cells. Until now, there has been little progress toward clinical application, although several investigators have recently published clinically approvable methods for large-scale ex vivo expansion of functional γδ T cells for therapeutic purposes. This review discusses the biology of γδ T cells with respect to innate immunotherapy of cancer with a focus on GBM, and explores graft engineering techniques in development for the therapeutic use of γδ T cells. © 2009 Springer Science+Business Media, LLC.