T LYMPHOCYTES Of the alpha/beta T-cell receptor (TCR) lineage mature in the thymus, where they undergo a series of differentiation, expansion and selection events(1-7). For normal T-cell ontogeny to occur, thymocytes must interact physically with cortical and medullary thymic stroma cells(8-10). In parallel, interactions of the thymic stromal cells with TCR-positive thymocytes are necessary for the development of the thymic medulla(10-12). Comparable requirements for the differentiation of the cortex have not been defined, however. Here me analyse mutant mouse strains to assess the function of early prothymocytes in the induction of the thymic cortex. We find that animals with a developmental block at the earliest stage of T-lineage commitment lack a functional thymic cortex. This abnormality could be corrected in fetal but not adult animals by transplantation of either fetal or adult wild-type haematopoietic stem cells. Thus a developmentally restricted interaction of fetal stromal cells with early prothymocytes is required for the induction of a cortical microenvironment. In addition, a normal thymic architecture is necessary for sustained T-cell ontogeny.