Decreased oxygen (O₂) levels activate hypoxia-inducible factor (HIF-1) to induce genes involved in glycolysis, glucose transport, erythropoiesis, and angiogenesis. Mutations in various HIF-1 subunits have contributed to our understanding of the role hypoxia plays during early embryonic development in general and the cardiovascular system in particular. We propose that HIF-1 is important for the generation, proliferation, maintenance, and differentiation of the early cardiovascular system. Understanding aberrations in these hypoxic responses is important since they contribute to serious human disease such as ischemia and tumorigenesis. In this review we will focus on the critical role of O₂ in regulating cardiovascular events during early embryonic development.