Reduction in uteroplacental perfusion (RUPP) during pregnancy is associated with abnormalities consistent with features of human preeclampsia (PE). Recent studies have shown that an imbalance of pro‐angiogenic factors and the anti‐angiogenic factor, sFlt‐1, exists in PE. While abnormalities in sFlt‐1 synthesis are thought to play a role in the pathogenesis of PE, the mechanisms that lead to its production are unclear. The purpose of this study was to determine the role of placental ischemia and hypoxia in mediating the increase in sFlt‐1. Plasma concentrations of sFlt‐1 in response to RUPP in pregnant rats are elevated (660±270 vs 82±26 pg/mL). In addition, we found sFlt‐1 to be significantly elevated in placentas from RUPP rats. Moreover, we report that sFlt‐1 from placental explants is higher in RUPP rats (2603±187 vs 2025±183 pg/ml) under normoxic conditions (6%O2). Finally, we found that placental explants from pregnant rats grown in hypoxic conditions (1%O2) enhanced the production of sFlt‐1 (4066±561 vs 2025±183 pg/ml). In summary, we found that plasma and placental sFlt‐1 production are significantly elevated in response to placental ischemia in pregnant rats, in placental explants from RUPP rats, and in placental explants from normal pregnant rats exposed to hypoxia. These data suggest that placental ischemia/hypoxia may be an important mechanism that leads to production of sFlt‐1 in preeclampsia.