The placenta plays a major role in feto-maternal communication and the maintenance of pregnancy. In early pregnancy, mononuclear cytotrophoblasts fuse to multinucleated syncytiotrophoblasts that cover the floating chorionic villi, or differentiate into extravillous trophoblasts (EVTs), which are capable of invading the endometrium and develop from anchoring villi. Impairment of trophoblast cell invasion into the endometrium causes serious complications during pregnancy, including hypertensive disorder of pregnancy (HDP), which is mainly caused by insufficient invasion by EVTs. Approximately 10 ％ of pregnant women experience HDP, the leading cause of maternal and perinatal morbidity and mortality. Our RNA-seq analysis using human placental tissues of HDP patients revealed the involvement of the endoplasmic reticulum (ER) stress signaling in HDP. ER stress may play a role in the maintenance of pregnancy, however, the excessive levels of ER stress could cause various human disorders, possibly including HDP. ER stress is capable of regulating the degree of trophoblast invasion, which is accompanied by changes in expression of high-temperature requirement A serine peptidase 1 (HTRA1). Further evidence shows that pharmacological induction of ER stress increases the secretion of HDP markers such as sFlt1. Our findings could lead to design novel therapeutic means to improve HDP.