Nutrient sensing is a fundamental process for life. In its absence, fast growing cells of the developing embryo and of expanding tumors would rapidly outstrip essential nutrients and die. In fact cells sense and respond to variations in the concentration of key nutrients. However, early on in evolution, oxygen sensing has emerged, as a central control mechanism of energy metabolism and vasculogenesis. At the heart of this regulatory system is the Hypoxia-Inducible Factor, HIF, which controls, among other gene products, the expression of VEGF-A and Angiopoïetin-2, two key angiogenic factors in vertebrates. This finding has placed the hypoxia-signaling pathway at the forefront of nutritional control. HIF controls glycolysis, intracellular pH (pHi), angiogenesis, cell migration and invasion, and so has become recognized as a strong promoter of tumor growth. We will highlight some of the HIF-induced gene products that participate in tumor adaptation, resistance and progression in a nutrient-depleted and acidic microenvironment. First we will demonstrate that the two HIF-induced 'BH3-only'- proteins (BNIP3, BNIP3L/NIX), in contrast to current belief, do not trigger cell death but, by inducing macro-autophagy, stimulate tumor cell survival. Second, we will show how tumor cells by expressing two HIF- dependent membrane-bound carbonic anhydrases, CAIX and CAXII, acidify the extracellular milieu, and ensure a more alkaline intracellular pH favoring migration, survival and growth in a hostile acidic microenvironment. Third, HIF-induced glycolysis in most hypoxic tumor cells is essential to ensure maintenance of ATP levels for growth and cell survival. Two MonoCarboxylate Transporters MCT-1 and MCT-4, stabilized in the plasma membrane by the common chaperon basigin/CD147, play a key role in cancer metabolism. We propose that appropriate exploitation of these HIF-regulated proteins and new validated cancer targets, which control exacerbated tumor metabolism and intracellular pH, will be at the forefront of anti-cancer therapy.