Cancer cells are characterized by high metabolic demand. The substrates in demand include oxygen, glucose, glutamine and lipids. Oxygen serves as a key substrate in cellular metabolism and bioenergetics. Hypoxia or low oxygen abundance is a common feature of the tumor microenvironment that occurs due to an imbalance in supply and demand. Many of the metabolic responses to hypoxia in both cancer cells and stromal cells are orchestrated by hypoxia-inducible factors (HIFs). In this review we summarize our current understanding of how HIFs modulate the metabolism of hypoxic cancer cells and immune cells, and how altered metabolism plays a role in cancer progression.