Lysosomes are crucial organelles responsible for degrading macromolecules and releasing their components as nutrients. They maintain a highly acidic pH (4.5-5.0) within their lumen, which is essential for their function. This pH gradient is generated by a proton-pumping V-type ATPase, which uses ATP to pump protons into the lysosome lumen. However, this process generates a transmembrane voltage, necessitating the movement of an ion to dissipate this voltage. The identity of this counterion remains controversial, with recent evidence suggesting ClC-7, a Cl/H⁺ antiporter, may play a significant role. Both the V-ATPase and the counterion transporter are likely key players in maintaining the lysosomal pH. Recent findings also indicate that lysosomal pH may be dynamically regulated in certain cell types, suggesting new avenues for understanding and potentially targeting lysosomal function in disease.Lysosomes are crucial organelles responsible for degrading macromolecules and releasing their components as nutrients. They maintain a highly acidic pH (4.5-5.0) within their lumen, which is essential for their function. This pH gradient is generated by a proton-pumping V-type ATPase, which uses ATP to pump protons into the lysosome lumen. However, this process generates a transmembrane voltage, necessitating the movement of an ion to dissipate this voltage. The identity of this counterion remains controversial, with recent evidence suggesting ClC-7, a Cl/H⁺ antiporter, may play a significant role. Both the V-ATPase and the counterion transporter are likely key players in maintaining the lysosomal pH. Recent findings also indicate that lysosomal pH may be dynamically regulated in certain cell types, suggesting new avenues for understanding and potentially targeting lysosomal function in disease.