Potassium-chloride co-transporter 2 (KCC2) is a member of cation-chloride co-transporters family, which expresses extensively in central nervous system. KCC2 is responsible for the maintenance of low concentration of intracellular chloride by excluding intracellular chloride outside the cells, which is the key mechanism of normal functions of inhibitory neurons. The down-regulation of KCC2 expression participates in the development and maintenance of several nervous system diseases and pain, and KCC2 expression is regulated by many factors. The mechanism of regulation of KCC2 is reviewed in this paper.