Reciprocal interactions between bone marrow derived precursor cells and the thymic environment lead to the generation of the complete repertoire of diverse and functional T cells. We have previously shown that p38 MAP kinase is activated in response to intrathymic signals in thymocytes. In this report we provide evidence that p38 MAP kinase activity is essential for pre-TCR-mediated transition of thymocytes; from the CD4(-) CD8(-) to the CD4(+) CD8(+) stage of development. In the absence of p38 MAP kinase activity differentiation of ap T cells, but not gamma delta T cells, was blocked.