A stage critical in mammalian development is embryo implantation. At this point, the blastocyst establishes a close interaction with the uterine tissues, a step necessary for its continued embryonic development. In many mammalian species, including man, uterine expression of the cytokine, leukemia inhibitory factor (LIF) is coincident with the onset of implantation and in mice LIF is essential to this process. The reasons for implantation failure have not been established. Here we show in LIF-deficient mice that up to the onset of implantation, changes in uterine cell proliferation, hormone levels, blastocyst localization, as well as expression of lactoferrin and Muc-1, do not differ from wild-types. However, the uterus fails to respond to the presence of embryos or to artificial stimuli by decidualizing. In mice, implantation and decidualization are induced by nidatory estrogen. We show that uterine expression of LIF is up-regulated by estrogen and LIF can replace nidatory estrogen at inducing both implantation and decidualization in ovariectomized mice. Implantation of LIF-deficient embryos in the LIF-deficient females, with normal development to term is rescued by i.p. injection of LIF. Transient expression of LIF on D4 of pregnancy is therefore only required to induce a state of receptivity in the uterus permitting embryo implantation and decidualization. LIF is neither required by the embryo for development nor for the maintenance of pregnancy.