Cancer cells are characterized by rapid proliferation and require adaptive metabolic responses to allow continued biosynthesis and cell growth in the setting of decreased oxygen (O₂) and nutrient availability. The hypoxia-inducible factors (HIFs) are a common link between adaptation to low O₂, changes in cancer metabolism, and malignant progression. The HIF-α subunits differentially regulate metabolic enzymes and other key factors involved in glycolysis, changes in redox status, and oxidative phosphorylation. Importantly, metabolic changes can, in turn, regulate HIF activity. Finally, changes in metabolism under hypoxia lead to important crosstalk between cancer cells and the stromal compartment of the microenvironment.