Cancer is caused by mutations that drive aberrant growth, proliferation, and invasion, thus overriding regulatory mechanisms that normally link these processes to organismal needs and cellular physiology. This imposes demands for the production of energy and biomass and for survival in microenvironments that are often nonphysiologic and nutrient-poor, which are met by rewiring of cellular metabolism. The resultant dependence of tumor cells on altered metabolism can induce sensitivity to specific metabolic perturbations that can be exploited for cancer therapy. Some cancers are caused by mutations that impart a novel function to metabolic enzymes, leading to the production of a tumor-promoting metabolite that is dispensable in normal cells, representing an ideal therapeutic target. Tumors can also exploit metabolic regulation of cellular immunity to evade antitumor immune responses, and deciphering this biology has revealed potential targets for therapeutic intervention. Here, we discuss a number of illustrative examples highlighting the therapeutic potential and the challenges of targeting metabolism for cancer therapy.