All rapidly growing cells must take up extracellular nutrients at an accelerated rate to support the anabolism required to double cell mass. Restricting nutrient access will thus limit cell proliferation. Moreover, because the mutations that occur in cancer cells make them metabolically inflexible, nutrient deprivation will be more detrimental to transformed than non-transformed cells. When nutrient limited, normal cells become quiescent and catabolic, entering a hibernation-like state. Cancer cells, in contrast, cannot respond adaptively to starvation and continue to try to grow, forcing themselves into a bioenergetic crisis. As a result of these differences in metabolic wiring, a therapeutic compound that triggers nutrient transporter loss would likely be an effective and selective cancer therapy. Sphingolipids have an evolutionarily conserved role as regulators of nutrient transporter surface expression. In heat stressed stressed yeast, sphingolipids cause nutrient permease down-modulation that protects cells by slowing growth. We found that ceramide and the sphingosine-like drug FTY720 trigger the rapid down-regulation of nutrient transporter proteins in a variety of mammalian cell types. Restricting nutrient access in this way is indeed more toxic to cancer cells than to normal cells. To better understand which oncogenic mutations confer sensitivity and resistance to sphingolipid-induced nutrient transporter loss, we compared the sensitivity of TSC2 wildtype and knockout fibroblasts to ceramide. TSC2-/- cells have constitutively high mTORC1 activity. The mTORC1 kinase complex is active in most cancer cells where it drives protein translation, glycolysis, and lipid synthesis. TSC2 is a critical negative regulator of mTORC1 under unfavorable growth conditions. Because they cannot reduce anabolism, TSC2-/- cells are hypersensitive to glucose withdrawal. Surprisingly, we found that TSC2-/- cells were resistant to death induced by sphingolipids. Although amino acid and glucose transporters were initially down-regulated, TSC2-/- cells mounted an exaggerated adaptive response to nutrient stress exhibiting a dramatic, mTORC1-dependent up-regulation of new transporter proteins. Patients heterozygous for inactivating mutations in TSC1 or TSC2 develop benign hamartomatous growths and we propose that this loss of tissue homeostasis might be due in part to the ability of TSC1/2 deficient cells to overcome nutrient or ceramide enforced limits on growth. Interestingly, these hamartomas do not progress to malignant disease. Consistent with this, we found that introducing the potently transforming H-RasV12 mutant reversed the survival advantage of TSC2-/- MEFs, apparently by increasing nutrient demand. These results support the idea that fully transformed cancer cells will be susceptible to drugs targeting transporter proteins. Along these lines, we are developing new analogs of FTY720. FTY720 is effective in multiple animal models of cancer, but cannot be used in human patients because it causes profound bradycardia by affecting sphingosine-1-phosphate receptors 1 and 3. We have found that FTY720’s effects on S1P receptors and nutrient transporter proteins are separable and unrelated. FTY720 analogs designed to lack S1P activity are effective anti-cancer agents both in vitro and in vivo. Moreover, these compounds show striking synergy with other compounds targeting the metabolic changes associated with cancer including mTORC1 activation. Together, these studies suggest that these novel compounds targeting multiple nutrient transporters simultaneously could prove to be safe and effective anti-cancer therapies.