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Targeting cancer metabolism for therapy has received much attention over the last decade with various small molecule inhibitors entering clinical trials. The present review highlights the latest strategies to target glucose and glutamine metabolism for cancer therapy with a particular emphasis on novel combinatorial treatment approaches.Inhibitors of glucose, lactate, and glutamine transport and the ensuing metabolism are in preclinical to clinical trial stages of investigation. Recent advances in our understanding of cell-intrinsic and cell-extrinsic factors that dictate dependence on these targets have informed the development of rational, synthetic lethality-based strategies to exploit these metabolic vulnerabilities.Cancer cells exhibit a number of metabolic alterations with functional consequences beyond that of sustaining cellular energetics and biosynthesis. Elucidating context-specific metabolic dependencies and their connections to oncogenic signaling and epigenetic programs in tumor cells represents a promising approach to identify new metabolic drug targets for cancer therapy.