The rationale for direct inhibition of the mutant enzyme relies on several observations: first, gliomas associated IDH mutations are located in hotspots within the enzyme’s active site; second, given their extremely high prevalence, the distinct DNA hypermethylation pattern and the persistence of IDH-mut clones, IDH mutations are considered an early oncogenic “driver” of LGGs; third, 2-HG showed in vitro similar cancer-promoting effects of the mutant IDH enzyme in a reversible fashion, emphasizing the pharmacological relevance of blocking the accumulation of this oncometabolite. The gene discussed is IDH2; the disease is cancer.