THE Ets-1 proto-oncogene(1) is a member of the Ets family of eukaryotic transcription factors(2-7). Members of this family play important roles in regulating gene expression in response to multiple developmental and mitogenic signals(4,5,8,9) Ets-1 is preferentially expressed at high levels in B and T cells of adult mice(10,11) and is regulated during both thymocyte development(11) and T-cell activation(12,13), To study the role of Ets-1 in T-cell development and function we have used the RAG-2(-/-) complementation system(14) and murine embryonic stem (ES) cells containing homozygous deletions in the Ets-1 gene (Ets-1(-/-)). Ets-1(-/-)-RAG-2(-/-) chimaeric mice displayed markedly decreased numbers of mature thymocytes and peripheral T cells. Ets-1(-/-) T cells expressed normal levels of CD3 and T-cell antigen receptor (TCR)-alpha/beta. However, they displayed a severe proliferative defect in response to multiple activational signals and demonstrated increased rates of spontaneous apoptosis in vitro. These findings demonstrate that Ets-1 is required for the normal survival and activation of murine T cells.