Antibody perturbation and gene knockout studies show that adhesion receptor modulation plays a critical role in peri-implantation mouse embryo and human cytotrophoblast differentiation. Deletion of beta 1 integrins leads to cell death in the inner cell mass of mouse embryos shortly after implantation in vivo or blastocyst outgrowth in vitro. In F9 embryonal carcinoma cells, deleting beta 1 also affects migration of parietal endoderm even on substrates for which the mutant cells express alternative receptors. Human cytotrophoblasts switch their integrin repertoire as they differentiate and invade the uterine interstitium and vasculature. Interestingly, cytotrophoblasts also transform their cell-cell adhesion molecule phenotype, expressing additional cadherins and immunoglobulin family members as they differentiate. Many of these modulations in adhesion phenotype are initiated early in the pre- and/or peri-implantation periods in human and mouse embryos. Therefore, they constitute important markers of normal progression for evaluating effects of environmental stress and for testing the hypothesis that abnormal switching of adhesion molecules characterizes a significant proportion of conceptuses that fail early in development.