Abstract Cancer cells are markedly different from normal cells with regards to how their metabolic pathways are used to fuel cellular growth and survival. Two basic metabolites that exemplify these differences through increased uptake and altered metabolic usage are glucose and glutamine. These molecules can be catabolized to manufacture many of the building blocks required for active cell growth and proliferation. The alterations in the metabolic pathways necessary to sustain this growth have been linked to therapeutic resistance, a trait that is correlated with poor patient outcomes. By targeting the metabolic pathways that import, catabolize, and synthesize essential cellular components, drug-resistant cancer cells can often be resensitized to anticancer treatments. The specificity and efficacy of agents directed at the unique aspects of cancer metabolism are expected to be high; and may, when in used in combination with more traditional therapeutics, present a pathway to surmount resistance within tumors that no longer respond to current forms of treatment. Cancer Res; 73(9); 2709–17. ©2013 AACR.