Cation-chloride cotransporters (CCCs) mediate the electroneutral transport of chloride, potassium and/or sodium across the membrane, and play important roles in human physiology and diseases. These transporters are primary targets for some of the most commonly prescribed drugs. As described in a recent paper in Nature, the Liao Lab (in collaboration with Dr. Liang Feng’s lab at Stanford University) determines the cryo-EM structure of the Na-K-Cl cotransporter NKCC1. Structural analyses, functional characterizations and computational studies reveal the ion-translocation pathway, ion-binding sites and key residues for transport activity. These results establish a framework for understanding the physiological functions of CCCs and interpreting disease-related mutations.