c-MYC and the hypoxia-inducible factors (HIFs) are critical factors for tumorigenesis in a large number of human cancers. While the normal function of MYC involves the induction of cell proliferation and enhancement of cellular metabolism, the function of HIF, particularly HIF-1, involves adaptation to the hypoxic microenvironment, including activation of anaerobic glycolysis. When MYC-dependent tumors grow, the hypoxic tumor microenvironment elevates the levels of HIF, such that oncogenic MYC and HIF collaborate to enhance the cancer cell's metabolic needs through increased uptake of glucose and its conversion to lactate. HIF is also able to attenuate mitochondrial respiration through the induction of pyruvate dehydrogenase kinase 1 (PDK1), which in part accounts for the Warburg effect that describes the propensity for cancers to avidly take up glucose and convert it to lactate with the concurrent decrease in mitochondrial respiration. Target genes that are common to both HIF and MYC, such as PDK1, LDHA, HK2, and TFRC, are therefore attractive therapeutic targets, because their coordinate induction by HIF and MYC widens the therapeutic window between cancer and normal tissues.