Fibroblast growth factors (FGFs) are thought to influence many processes in vertebrate development because of their diverse sites of expression and wide range of biological activities in in vitro culture systems. As a means of elucidating embryonic functions of FGF-4, gene targeting was used to generate mice harboring a disrupted Fgf4 gene. Embryos homozygous for the null allele underwent uterine implantation and induced uterine decidualization but did not develop substantially thereafter. As was consistent with their behavior in vivo, Fgf4 null embryos cultured in vitro displayed severely impaired proliferation of the inner cell mass, whereas growth and differentiation of the inner cell mass were rescued when null embryos were cultured in the presence of FGF-4 protein.