The project aimed to provide a mechanistic understanding of the effect of endoplasmic reticulum (ER) stress on the differentiation of trophoblast stem cells (TSCs), placental development, and subsequent pregnancy outcome. To address this question, I first used an in vitro mouse TSC model. Morphological observations suggest that upon ER stress, TSCs lose stemness by differentiating into specialized trophoblast cell subtypes. Second, I used an in vivo Eif2s1tm1RjK mouse model that exhibits chronic ER stress.Third, I induced ER stress using a more physiological stress inducer in pre-implantation wild-type embryos for 48h in vitro, which results in a significantly smaller TE stem cell pool, and increased expression of Grp78, Atf4 and Atf6a UPR markers. The phenotype was partially rescued by addition of a chaperone to the culture medium. In conclusion, both the in vitro and in vivo models demonstrate that ER stress perturbs differentiation of TS cells at the blastocyst stage, with consequences for placental morphogenesis and fetal development. Pilot studies using a stress-relieving chaperone indicate that therapeutic interventions may be possible.