Therapeutic strategies designed to target cancer metabolism are an area of intense research. Antimetabolites, first used to treat patients in the early twentieth century, served as an early proof of concept for such therapies. We highlight strategies that attempt to improve on the anti-metabolite approach as well as new metabolic drug targets. Some of these targets have the advantage of a strong genetic anchor to drive patient selection (isocitrate dehydrogenase 1/2, Enolase 2). Additional approaches described here derive from hypothesis-driven and systems biology efforts designed to exploit tumor cell metabolic dependencies (fatty acid oxidation, nicotinamide adenine dinucleotide synthesis, glutamine biology).