One of the key homeostatic mechanisms connecting vascular oxygen supply and metabolic demand is hypoxia’s regulation of angiogenesis. New insights into this process have emerged thanks to the molecular characterization of angiogenic pathways, the discovery of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydroxylases as a family of dioxygenases that regulate HIF by oxygen availability. Several pro- and antiangiogenic factors influence the mechanisms that govern angiogenesis in hypoxia or a hypoxic habitat. Although HIFs are the primary inducers of angiogenesis, it is becoming increasingly necessary to understand the function of interacting proteins to comprehend the hypoxia response’s angiogenic processes fully. The HIF, PI3K, MAPK, and NFB pathways are all activated by hypoxia in cancer cells, and these pathways all interact with one another, creating positive and negative feedback loops that either amplify or attenuate the effects of hypoxia. In addition, understanding how tumor cells create their own vasculature is crucial for identifying alternate methods of suppressing tumor growth by blocking the growth-triggering mechanisms of increased vascular supply via angiogenesis. We summarize these studies here, along with HIF’s function in normal, adaptive, and malignant angiogenic processes. We also talk about how the tumor phenotype is affected by the oncogenic activation of many, physiologically related hypoxic mechanisms. New doors for the discovery of therapies targeting hypoxic tumor cells and the hypoxic microenvironment will open up as our knowledge of hypoxia’s function in angiogenesis.