Simple SummaryIsocitrate dehydrogenase (IDH) is the most mutated metabolic gene in human cancer. Mutations in this gene have been identified in a high percentage of gliomas, in acute myeloid leukemia (AML) and in many other malignancies. MutantIDHcauses tumour initiation, possibly through accumulation of the oncometabolite D2-hydroxyglutarate, a product of normal metabolism with limited known function in mammals. Many studies have tried to elucidate the biological consequences of mutant IDH and to find effective inhibitors targeting this enzyme. This review delves into the cellular, biochemical and molecular consequences of mutant IDH and the therapeutic strategies for treating IDH mutant cancers.AbstractAltered metabolism is a common feature of many cancers and, in some cases, is a consequence of mutation in metabolic genes, such as the ones involved in the TCA cycle. Isocitrate dehydrogenase (IDH) is mutated in many gliomas and other cancers. Physiologically, IDH converts isocitrate to α-ketoglutarate (α-KG), but when mutated, IDH reduces α-KG to D2-hydroxyglutarate (D2-HG). D2-HG accumulates at elevated levels in IDH mutant tumours, and in the last decade, a massive effort has been made to develop small inhibitors targeting mutant IDH. In this review, we summarise the current knowledge about the cellular and molecular consequences of IDH mutations and the therapeutic approaches developed to target IDH mutant tumours, focusing on gliomas.