Chloride is a critical component of all living cells. It is also the single most dominant diffusible anion inside of most cells-the others are mostly impermeable organic anions. Since cytoplasmic electroneutrality is maintained under normal physiological environment, changes in cellular chloride level is accompanied by total cell solute content. The cation chloride cotransporters (CCC) protein family is involved in the electroneutral movement of ions across the cell membrane. The K-Cl cotransporters mediate the coupled movement of K+ and Cl- ions across the cell membranes. This transport process is involved in the regulatory volume decrease in response to cell swelling in red cells and vectorial movement of Cl- ions across the kidney epithelia. The net direction of this transport is out of the cells. At least four isoforms of KCC identified (KCC1, KCC2, KCC3, and KCC4) have been identified and functionally characterized. KCC are predicted to have the same protein structure: 12 transmembrane domains with a large extracellular loop with potential N-glycosylation sites, and the cytoplasmic N and C-termini. KCC3 is ~77% identical to KCC1. It is highly expressed in brain, heart, skeletal muscle, and kidney. KCC3 is modulated by VEGF and TNF-alpha.