gammadelta T cells contribute to host immune competence uniquely. This is most likely because they have distinctive antigen-recognition properties. While the basic organization of gammadelta T-cell receptor (TCR) loci is similar to that of alphabeta TCR loci, there is a striking difference in how the diversity of gammadelta TCRs is generated. gammadelta and alphabeta T cells have different antigen-recognition requirements and almost certainly recognize a different set of antigens. While it is unclear what most gammadelta T cells recognize, the non-classical major histocompatibility complex class I molecules T10 and T22 were found to be the natural ligands for a sizable population (0.2-2%) of murine gammadelta T cells. The recognition of T10/T22 may be a way by which gammadelta T cells regulate cells of the immune system, and this system has been used to determine the antigen-recognition determinants of gammadelta T cells. T10/T22-specific gammadelta T cells have TCRs that are diverse in both V gene usage and CDR3 sequences. Their Vgamma usage reflects their tissue origin, and their antigen specificity is conferred by a motif in the TCR delta chain that is encoded by V and D segments and by P-nucleotide addition. Sequence variations around this motif modulate affinities between TCRs and T10/T22. That this CDR3 motif is important in antigen recognition is confirmed by the crystal structure of a gammadelta TCR bound to its ligand. The significance of these observations is discussed in the context of gammadelta T-cell biology.