Chloride is a critical component of all living cells. It is also the single most dominant diffusible anion inside of most cells. The cation chloride cotransporters (CCC) protein family is involved in the electroneutral movement of ions across the cell membrane. It includes the thiazide-sensitive Na+Cl- cotransporters (NCC or TSC), the loop diuretics-sensitive Na+K+Cl- (NKCC) cotransporters (NKCC1/CCC1/BSC2 and NKCC2/CCC2/BSC1) and the K+Cl- cotransporters (KCC1-4). These co-transporters share a common predicted membrane topology, with 12 TM domains (~500aa), and long hydrophilic, intracellular N- and C-termini containing regulatory phosphorylation sites. NKCC transport Na, K, and Cl ions into and out of a wide variety of epithelial and non-epithelial cells. The transport process is characterized by electroneutrality and inhibition by the loop diuretic bumetanide, benzametanide and furosemide. Unlike NKCC1, NKCC2 (human 1099aa, rat/mouse 1095aa; calculated mol size of ~121kD; actual size ~150kD; ~45% identity with NKCC1) is most strongly expressed in the kidney and macula densa. NKCC2 plays a critical role in transcellular absorption of Na+Cl- by the medullary and cortical TALH, and a secondary role in the paracellular transport of Na-Ca and Mg. Mutations in the NKCC2 gene result in Bartter's syndrome, an inherited disease characterized by hypokalemic metabolic alkalosis, hypercalciuria, salt wasting and volume depletion.