The transcription factor serum response factor (SRF) controls the expression of genes involved in cellular proliferation and differentiation. Interestingly, SRF also promotes cell survival by regulating the expression of antiapoptotic genes. In in vitro differentiating murine embryonic stem (ES) cells, SRF deficiency leads to increased apoptosis. Loss of SRF correlates with impaired expression of the antiapoptotic Bcl‐2 and Bcl‐xl genes. SRF binds the Bcl‐2 promoter in vivo and activates Bcl‐2 transcription. Reconstituting Bcl‐2 in Srf(−/−) ES cells rescues these cells from apoptosis, demonstrating that SRF‐dependent Bcl‐2 expression is critical for ES cell survival. At the multicellular level, SRF deficiency leads to impaired cavitation and reduced Bcl‐2 expression in embryoid bodies (EBs) and inappropriate apoptosis in both EBs and pregastrulation mouse embryos. Thus, our data from genetic and cellular studies uncover SRF‐regulated Bcl‐2 expression as a novel mechanism that is important for cell survival during early murine embryogenesis.