Isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle catalyzes the conversion of isocitrate to α-ketoglutarate and the reduction of NAD+ or NADP+ to NADH or NADPH. According to the conformational characteristics, NADP-dependent IDH can be divided into homodemeric IDH and monomeric IDH, and they play a key role in the organisms for their energy metabolism, biosynthesis and resistance to oxidation stress. During growth on the poor carbon sources, the partition of carbon flux between TCA cycle and glyoxylate bypass is vitally regulated by the reversible phosphorylation of IDH. Therefore, IDH is one of the best models for investigating the relationships between protein structure and function, the mechanisms of enzyme catalysis and regulation, and the functional evolution of proteins.