In cattle, establishment of pregnancy in cattle begins at the conceptus stage (embryo/fetus and associated extraembryonic membranes) and includes pregnancy recognition signaling, implantation, and the onset of placentation. Survival and growth of the preimplantation blastocyst and elongating conceptus requires embryotrophic factors provided by endometrium of the uterus. However, the critical physiological pathways and genes that govern pregnancy establishment and success are not well elucidated. Serial embryo transfer was previously used to classify heifers as high-fertile (HF), subfertile (SF), or infertile (IF). Pregnancy rate was substantially higher in HF and SF than IF heifers on d 17, and elongating conceptuses were about 2-fold longer in HF than SF heifers. Transcriptional profiling detected relatively few differences in the endometrium of nonpregnant HF, SF, and IF heifers. In contrast, there was a substantial difference in the transcriptome response of the endometrium to pregnancy between HF and SF heifers. Considerable deficiencies in pregnancy-dependent biological pathways associated with extracellular matrix structure and organization as well as cell adhesion were found in the endometrium of SF animals. Distinct gene expression differences were also observed in conceptuses from HF and SF animals, with many of the genes decreased in SF conceptuses known to be embryonic lethal in mice due to defects in embryo and/or placental development. Analyses of biological pathways, key players, and ligand-receptor interactions based on transcriptome data divulged substantial evidence for dysregulation of conceptus-endometrial interactions in SF animals. These results support the ideas that the uterus impacts conceptus survival and programs conceptus development, and ripple effects of dysregulated conceptus-endometrial interactions elicit loss of the post-elongation conceptus in SF cattle during the implantation period of pregnancy. These studies provide an important foundation to understand implantation and early placentation-phase pregnancy loss and develop genetic and physiological approaches to improve the outcome of natural and assisted pregnancies.