Notch signaling is essential for vascular morphogenesis in mice. This study investigates the role of the Notch4 gene in embryonic development. Notch4-deficient mice were viable and fertile, but exhibited no obvious mutant phenotype. However, Notch4 null mutation genetically interacted with a mutation in the Notch1 gene, indicating partial functional redundancy between the Notch1 and Notch4 genes during embryogenesis. Double mutant embryos with mutations in both Notch1 and Notch4 genes showed severe defects in angiogenic vascular remodeling, affecting the embryo, yolk sac, and placenta. Analysis of Notch ligand gene expression patterns revealed that only the Dll4 gene was expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. These results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling. While the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice. The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism that plays a critical role in vascular development and homeostasis. The Notch4 gene is primarily expressed in vascular endothelial cells during early embryogenesis in mice. The Notch1 and Notch4 genes have partially overlapping roles during embryogenesis, and their mutations lead to severe vascular defects. The Notch signaling pathway is required for angiogenic vascular remodeling. The Dll4 gene encodes the probable ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. The Notch signaling pathway is essential for vascular development in embryos and maintenance of vascular homeostasis in adults. The Notch1 and Notch4 genes have partial functional redundancy, and their mutations lead to severe vascular defects. The Notch signaling pathway is essential for vascular development and homeostasis.Notch signaling is essential for vascular morphogenesis in mice. This study investigates the role of the Notch4 gene in embryonic development. Notch4-deficient mice were viable and fertile, but exhibited no obvious mutant phenotype. However, Notch4 null mutation genetically interacted with a mutation in the Notch1 gene, indicating partial functional redundancy between the Notch1 and Notch4 genes during embryogenesis. Double mutant embryos with mutations in both Notch1 and Notch4 genes showed severe defects in angiogenic vascular remodeling, affecting the embryo, yolk sac, and placenta. Analysis of Notch ligand gene expression patterns revealed that only the Dll4 gene was expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. These results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling. While the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice. The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism that plays a critical role in vascular development and homeostasis. The Notch4 gene is primarily expressed in vascular endothelial cells during early embryogenesis in mice. The Notch1 and Notch4 genes have partially overlapping roles during embryogenesis, and their mutations lead to severe vascular defects. The Notch signaling pathway is required for angiogenic vascular remodeling. The Dll4 gene encodes the probable ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. The Notch signaling pathway is essential for vascular development in embryos and maintenance of vascular homeostasis in adults. The Notch1 and Notch4 genes have partial functional redundancy, and their mutations lead to severe vascular defects. The Notch signaling pathway is essential for vascular development and homeostasis.