Our current working model incorporates features from both the previously accepted models of intrathymic differentiation and attempts to fit some of the more recent data regarding functional differentiation, as well as the fact that our understanding of the non-lymphoid components is only marginal at best. 1. There is indeed a high level of cell death in the cortex (in the Ly1, 2, 3+/L3T4+ subpopulation). However, a small proportion of cells, perhaps the blasts with the same phenotype, escape the selective environment of the cortex and migrate into the medulla. Much of the cellular division in the thymus is either inappropriate or non-productive (discussed above). This is further supported by the recent indication that several cDNA clones derived from a thymocyte library have defective reading frames resulting in incomplete genetic coding for the beta chain of the T cell receptor molecule (Hedrick et al. 1984). 2. The" cortical" versus" medullary" phenotypes fail to distinguish immature versus mature (functional) subsets. The dLy1 cells, which are among the most immature thymocytes, as discussed above, are at least partially cortisone resistant and enriched in the PNA/NAg cells (Fowlkes et al., manuscript in preparation). Furthermore, low Thy-1 cells, a type of cell usually expected to be a mature, medullary thymocyte, are seen at the cortical, subcapsular sites as well as in the medulla (van Ewijk et al. 1981). 3. The dLy1 intrathymic progenitor cells appear to be radioresistant but capable of sustaining only limited self-renewal in irradiated thymi (Basch et al. 1978, Sharrow et al. 1983). The dLy1 cells have already been depleted from the intrathymic population when the peak of the first wave of cellular regeneration is detected in irradiation chimeras (Sharrow et al. 1983). 4. Thymocytes with the dLy1 phenotype are proliferative, subcapsular (outer cortical) cells that represent a thymocyte progenitor pool which can be demonstrated to differentiate into Ly1, 2+; L3T4+ cells in vitro (Ceredig et al. 1983c, Fowlkes et al. 1984). In addition, the finding that the dLy1 cells can be seen as a high proportion of cells early in graft repopulation supports the concept that adult thymocyte differentiation follows the same pattern seen in fetal ontogeny. Thus an earlier suggestion that the fetal dLy1 cells would give rise directly to cells with a mature bLy1 phenotype (Mathieson et al. 1981) may be less likely. However, we may have been examining only one of two intrathymic progenitor subsets by the isolation of the dLy1 cells.(ABSTRACT TRUNCATED AT 400 WORDS)