Increasing evidence points to multiple pathways of T lymphocyte development. The well characterized thymus-dependent pathway gives rise to T cells bearing TCRαβheterodimers and either CD4 or CD8αβco-receptors. T cells of this lineage populate peripheral lymphoid compartments including lymph nodes, spleen, skin, and Peyer's patches. By comparison, factors which govern extrathymic T cell development are poorly understood. A variety of experiments have shown that intestinal intraepithelial lymphocytes (IELs) develop outside of the thymic environment, e.g., in the gut of nude, SCID, andβ2m-/- mutant mice, and after transplanting bone marrow or fetal liver cells into irradiated thymectomized adult mice. This review focuses on the role of the CD3-ζsubunit in the development of both thymically and extrathymically derived T cells as determined by gene-targeting experiments in mice. Data from these and other T cell-related mutations continue to define crucial stages in thymocyte differentiation. Most interestingly, CD3-ζmutant mice contain a unique population of intestinal IELs that develops independently of thymic selective processes and expresses a novel TCR/CD3 complex.