THE Ets-1 proto-oncogene is a member of a transcription factor family characterized by homology to the v-ets oncogene(1-4). In adult mice, Ets-1 is expressed predominantly in lymphoid cells where it has been implicated in regulating transcription of lymphocyte-specific genes(5-7). Following T-cell activation, the specific DNA binding activity of Ets-1 is inactivated by transient phosphorylation, suggesting a function in the transition from the resting to activated state(8,9). Ets-1 has also been suggested to cooperate with the AP-1 transcription factor complex to mediate cellular growth factor responses(4). Here we show, by using RAG-2-deficient blastocyst complementation(10), that Ets-1 deficiency has dramatic, but different, effects on development and function of T- and B-lineage cells, Ets-1-deficient T cells were present in reduced numbers and were highly susceptible to cell death in vitro. In contrast, Ets-1-deficient B cells were present in normal numbers but a large proportion were IgM plasma cells, Our data demonstrate that Ets-1 is essential for maintenance of the normal pool of resting T- and B-lineage cells.