Preeclampsia (PE) is a life-threatening complication of human pregnancy. Research in the field has identified many factors that are associated with PE, and in general these factors are regarded as villains in pregnancy health. We have been focusing on a protease that is not well expressed in any tissues except the placenta; it is also detected in the maternal circulation from early stages of pregnancy to term because of placental secretion. In PE, especially in the early-onset subtype, this enzyme is significantly elevated in the placenta as well as in the maternal circulation. Our studies strongly suggest that high levels of this protease circulating in the maternal blood but derived from the placenta may disturb maternal vascular homeostasis and contribute to the development of PE. To understand the dilemma as to why the placenta needs to make such a seemingly “destructive” factor that is not produced/wanted by any other organs in the body, we investigated its role in placental development using a number of approaches including derivation and differentiation of placental stem cells. Our results to date suggest that this villain enzyme which is so closely associated with PE is actually critical for human trophoblast differentiation and function. In this talk I will discuss our recent studies in this area, and I will also share our research on the potential utility of this enzyme in early detection of PE including the late-onset subtype which occurs far more frequently than the early-onset cases but are more difficult to detect pre-symptomatically.