Elevated circulating soluble fms-like tyrosine kinase 1 (sFLT-1) is associated with the development of the clinical signs and symptoms of preeclampsia. Placental ischemia has been suggested as one of the etiological factors that mediate increased sFLT-1 production in patients with preeclampsia, but definitive evidence for this hypothesis was lacking. Makris et al. demonstrate that inducing placental ischemia in primates is sufficient to induce sFLT-1 upregulation and the clinical signs and symptoms of preeclampsia.