This review focuses on the structure and function of the branchial chloride cell in freshwater fishes. The mitochondria-rich chloride cell is believed to be the principal site of trans-epithelial Ca2+ and Cl- influxes. Though currently debated, there is accruing evidence that the pavement cell is the site of Na+ uptake via channels linked electrically to an apical membrane vacuolar H(+)-ATPase (proton pump). Chloride cells perform an integral role in acid-base regulation. During conditions of alkalosis, the surface area of exposed chloride cells is increased, which serves to enhance base equivalent excretion as the rate of Cl-/HCO3- exchange is increased. Conversely, during acidosis, the chloride cell surface area is diminished by an expansion of the adjacent pavement cells. This response reduces the number of functional Cl-/HCO3- exchangers. Under certain conditions that challenge ion regulation, chloride cells proliferate on the lamellae. This response, while optimizing the Ca2+ and Cl- transport capacity of the gill, causes a thickening of the blood-to-water diffusion barrier and thus impedes respiratory gas transfer.