There is incomplete penetrance to Tgfb1 knockout phenotypes. About 50% of Tgfb1 homozygous mutant (Tgfb1^−/−) and 25% of Tgfb1 heterozygous (Tgfb1^+/−) embryos die during embryogenesis. In a mixed NIH/Ola × C57BL/6J/Ola × 129 background partial embryonic lethality of the Tgfb1^−/− embryos occurs due to defective yolk sac vasculopoiesis and/or hematopoiesis. We show here that on a predominantly CF‐1 genetic background, lack of TGFβ1 causes a pre‐morula lethality in about 50% of the null embryos. This partial lethality is not reversed by transfer of Tgfb1^−/− embryos to Tgfb1^+/+ hosts. The extent of embryonic lethality in Tgfb1^−/− embryos ranges in a background dependent manner from 20% to 100%. Based on these and other studies it is clear that TGFβ1 acts at two distinct phases of embryogenesis: pre‐implantation development and yolk sac vasculogenesis/hematopoiesis. The susceptibility for the pre‐implantation lethality depends on a small number of genetic modifiers since a small number of backcrosses onto the high susceptibility strain C57BL/6 leads to complete penetrance of the lethality. Mol. Reprod. Dev. 52:341–349, 1999. © 1999 Wiley‐Liss, Inc.