Abstract Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) bind to the receptor guanylyl cyclase (GC)-A, leading to diuresis, natriuresis, and blood vessel dilation. In addition, ANP and BNP have various angiogenic properties in ischemic tissue. When breeding mice devoid of GC-A, we noted significant skewing of the Mendelian ratio in the offspring, suggesting embryonic lethality due to knockout of GC-A. Consequently, we here investigated the roles of endogenous ANP and BNP in embryonic neovascularization and organ morphogenesis. Embryos resulting from GC-A−/− × GC-A+/− crosses developed hydrops fetalis (HF) beginning at embryonic day (E)14.5. All embryos with HF had the genotype GC-A−/−. At E17.5, 33.3% (12 of 36) of GC-A−/− embryos had HF, and all GC-A−/− embryos with HF were dead. Beginning at E16.0, HF-GC-A−/− embryos demonstrated poorly developed superficial vascular vessels and sc hemorrhage, the fetal side of the placenta appeared ischemic, and vitelline vessels on the yolk sac were poorly developed. Furthermore, HF-GC-A−/− embryos also showed abnormal constriction of umbilical cord vascular vessels, few cardiac trabeculae and a thin compact zone, hepatic hemorrhage, and poor bone development. Electron microscopy of E16.5 HF-GC-A−/− embryos revealed severe vacuolar degeneration in endothelial cells, and the expected 3-layer structure of the smooth muscle wall of the umbilical artery was indistinct. These data demonstrate the importance of the endogenous ANP/BNP-GC-A system not only in the neovascularization of ischemic tissues but also in embryonic vascular development and organ morphogenesis.