Preeclampsia is a pregnancy disorder characterized by malperfusion of the placenta and the release of soluble factors into the circulation. These soluble factors, such as fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG), cause maternal vascular endothelial dysfunction, leading to hypertension and multiorgan damage. Once preeclampsia is diagnosed, there is no curative treatment other than delivery. No drugs have been developed that affect the progression of the disease. We previously reported, in several pre-clinical experimental models, that proton pump inhibitors (PPIs) ameliorate pathophysiological molecules of preeclampsia including sFlt-1 and sENG secreted from primary trophoblasts. PPIs also mitigated endothelial dysfunction induced by tumor necrosis factor-alpha. We also showed that esomeprazole, one of the PPIs, suppressed hypertension in a pregnant mouse model of preeclampsia transduced with placenta-specific overexpression of the human sFlt-1 gene (Onda et al., Hypertension. 2017). Given the safety of PPIs during pregnancy (N Engl J Med. 2010), they are sometimes used for gastric reflux symptoms in pregnant women. In this presentation, I will summarize the research on the relationship between PPIs and preeclampsia originating from our report, review basic, epidemiological, and clinical studies that have been conducted recently, and mention the potential of PPIs in the prevention or treatment of preeclampsia.