Precise control of cellular Cl⁻ transport is necessary for many fundamental physiological processes. For example, the intracellular concentration of Cl⁻, fine-tuned through the coordinated action of cellular Cl⁻ influx and efflux mechanisms, determines whether a neuron’s response to GABA is excitatory or inhibitory. In epithelia, synchrony between apical and basolateral Cl⁻ flux, and transcellular and paracellular Cl⁻ transport, is necessary for efficient transepithelial Cl⁻ reabsorption or secretion. In cells throughout the body, coordination of Cl⁻ entry and exit mechanisms help defend against changes in cell volume. The Na-K-Cl and K-Cl cotransporters of the SLC12 gene family are important molecular determinants of Cl⁻ entry and exit, respectively, in these systems. The WNK serine-threonine kinase family, members of which are mutated in an inherited form of human hypertension, are components of a signaling pathway that coordinates Cl⁻ influx and efflux through SLC12 cotransporters to dynamically regulate intracellular Cl⁻ activity.