 Cells maintain a narrow physiological pH by exchanging intracellular bicarbonate for extracellular chloride. Here, authors determine the CREOM structures of human-anion exchanger 2, AE2, in five major operating states and one transitional state, to collectively demonstrate the process of pH balancing. This article was authored by Qing Zhong, Li Anjian, Decheng Yao, and others.