A fundamental function of the vasculature is to deliver oxygen to tissues and organs. The cells that make up the vasculature also require oxygen, and are acted upon by oxygen in direct and indirect ways that can have significant effects on acute and chronic vascular function and morphology. The role that oxygen, or its absence, plays in defining the biology of the vasculature is thus of critical importance, yet remains an area about which there are many gaps in knowledge and understanding. Oxygen-associated paracrine mechanisms can drive vascular processes such as angiogenesis. The vasculature can also directly sense blood oxygen levels and differentially translate this information into rapid vasoconstriction responses in some vascular beds, and vasodilation in others. Furthering our understanding of how oxygen and hypoxia affect the vasculature may lead to greater insights into the mechanisms and pathogenesis of disease processes involving the vasculature, and lead to new therapeutic paradigms.