The use of cytolytic effector cells as therapy for malignant disease has been a central focus of basic and clinical research for nearly 2 decades. Since the original descriptions of in vitro lymphocyte-mediated cytotoxicity against human tumor cells, there have been numerous attempts to exploit such observations for therapeutic use, with decidedly mixed results. Most studies have focused on the role of either natural killer cells or cytotoxic CD8+ αβ T cells as the primary mediators of antitumor cytotoxicity, and until recently little attention has been paid to the role of γδ T cells in this capacity. This is partially due to a lack of understanding of the mechanisms of γδ T-cell immune responses to tumors, as well as the practical problem of obtaining a sufficient number of γδ T cells for clinical-scale administration. In this article, we discuss the biological and clinical rationale for developing γδ T cell-based immunotherapies for the treatment of a variety of malignant conditions. It is our view that infusing supraphysiological numbers of tumor - reactive γδ T cells-either in the autologous or allogeneic setting-might be used to restore or augment innate immune responses against malignancies. Accordingly, we will also discuss how we and others are working to overcome some of the practical limitations that have so far limited the direct clinical delivery of highly purified human γδ T cells for the treatment of both hematologic and solid tumors. © 2005 American Society for Blood and Marrow Transplantation.