Diabetes and its complications are a major public health burden in the developed world. The major cause of diabetic complications is abnormal growth of new blood vessels. This dysfunctional neovascularization results in significant morbidity and mortality in patients with diabetes and, as such, is a major focus of basic and clinical investigation. It has become clear that hyperglycemia disrupts tissue-level signaling in response to hypoxia and ischemia, impairs the vasculogenic potential of circulating stem cells and fundamentally alters the structure and function of key neovascularization proteins, including hypoxia-inducible factor-1. These mechanistic and pathophysiologic studies have revealed new therapeutic targets to restore normal neovascularization and to ameliorate and prevent diabetic vascular complications.