THE product of the vav proto-oncogene(1), p95(vav) or Vav, is tyrosine phosphorylated upon stimulation of T and B cells by antigen(2-4) and other(5-8) receptors, and contains motifs associated,vith signal transduction(1,9-11). To determine its role in vivo, we used vav-gene-targeted embryonic stem(12) cells and RAG-2(-/-) blastocyst complementation(13). The vav(-/-)-RAG-2(-/-) chimaeras displayed thymic atrophy with reduced numbers of peripheral T cells. Whereas the total number of B cells was normal, the subset of peritoneal B-1 (CD5(+))(14) cells was missing. The vav(-/-) T and B cells were hyporeactive when stimulated through antigen receptors, but vav(-/-) T cells proliferated on exposure to phorbol ester and calcium ionophore(15), whereas B cells responded normally to bacterial mitogen, lipopolysaccharide or the CD40 ligand(16-18). Thus, we have established here a functional role for vav in the control of T- and B-cell development and activation.