Impairment of oxygen supply occurs in many pathological situations. In the case of cancer, both chronic and acute hypoxic areas are found in the tumor. Tumor hypoxia is associated with poor clinical prognoses and is correlated with tumor growth and metastasis development. Pyruvate is a common metabolite, as it is an end-product of glycolysis and an energy substrate for the mitochondrial Krebs cycle. It is also well known for its protective properties against stressful conditions, particularly hypoxia. Its presence determines cellular fate when there is a lack of oxygen. Interestingly, pyruvate metabolism is altered during cancer development. For years, this was assumed to be a consequence of malignant transformation. However, it now is becoming clear that pyruvate could contribute to cancer progression. The role of pyruvate during hypoxia has been widely studied in non-tumor tissues and cells; it is less documented whether or not the protective effect of pyruvate could also take place in cancer cells. If so, pyruvate might be deleterious for cancer patients. The present paper reviews data that highlight the role of pyruvate in cancer cells and tumors during hypoxic stress.