T lymphocytes are classified into 2 subsets based on their T-cell receptor (TCR) expression. The vast majority of T cells expresses an alphabeta TCR heterodimer. These alphabeta T cells recognize antigenic peptides presented by MHC class I (for CD8(+) T cells) or MHC class II molecules (for CD4(+) T cells). Concepts of cancer immunotherapy are mostly concerned with activation of these MHC-restricted alphabeta T cells. Until recently, a numerically small subset of T cells, which expresses an alternative TCR composed of a CD3-associated gammadelta heterodimer, has received far less attention as a potential agent in cancer therapy. These gammadelta T cells share with alphabeta T cells certain effector functions such as cytokine production and potent cytotoxic activity but recognize different sets of antigens, usually in a non-MHC-restricted fashion. Different subsets of human gammadelta T cells recognize stress-inducible MHC class I-related molecules frequently expressed on epithelial tumor cells or phosphorylated metabolites which can be generated by tumor cells. In line with this, many tumor cells are highly susceptible to gammadelta T-cell mediated lysis. In our article, we summarize the available evidence for a contribution of human gammadelta T cells in tumor defense and discuss potential strategies for the immunotherapy of tumors based on the endogenous activation and/or adoptive transfer of tumor-reactive gammadelta T lymphocytes. (c) 2004 Wiley-Liss, Inc.