To test whether T and B cell differentiation can proceed across species barriers, rat fetal liver (FL) cells were used to reconstitute SCID mice. Provided that the hosts were conditioned with light irradiation, i.v. injection of FL cells caused near-complete repopulation with rat-derived lymphohematopoietic cells, including myeloid and erythroid cells, Ia+ cells of the macrophage/dendritic cell lineages, and mature T and B cells. In keeping with the known hypersensitivity of SCID cells to irradiation, host hematopoietic cells in the chimeras were almost undetectable, even with hosts exposed to as low as 250 rad. In the case of T cells, the distribution of immature and mature cells in the thymus of rat FL----SCID chimeras closely resembled the normal rat thymus in terms of architecture and expression of CD4, CD8, and alpha beta-TCR molecules. Thymopoiesis was followed by the appearance of large numbers of typical rat CD4+ and CD8+ cells in spleen and lymph nodes. These organs also contained substantial numbers of rat B (mu+) cells. The data thus indicate that the xenogeneic environment of SCID mice is fully capable of sustained de novo differentiation of rat T and B cells.