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Abstract Isocitrate dehydrogenases play important roles in cellular metabolism and cancer. This review will discuss how the roles of isoforms 1 and 2 in normal cell and cancer metabolism are distinct from those of isoform 3. It will also explain why, unlike 1 and 2, mutations in isoform 3 in tumor are not likely to be driver ones. A model explaining two important features of isocitrate dehydrogenases 1 and 2 mutations, their dominant negative effect and their mutual exclusivity, will be provided. The importance of targeting these mutations and the possibility of augmenting such therapy by targeting other cancer-related pathways will also be discussed.