Lysosomes are terminal organelles in the endocytic pathway that digest macromolecules and release their components as nutrients. They maintain a highly acidic pH (4.5-5.0) through the activity of a V-type ATPase, which uses ATP to pump protons into the lysosome lumen. This process generates a transmembrane voltage, requiring the movement of a counterion (either a cation or anion) to dissipate the voltage and allow net proton transport. Recent studies suggest that ClC-7, a Cl⁻/H⁺ antiporter, may be involved in this process, though its exact role remains unclear. The V-ATPase is electrogenic, generating a voltage that must be dissipated by counterion movement. The counterion pathway is crucial for maintaining lysosomal pH, with anion and cation permeabilities both contributing. Studies in isolated lysosomes and intact cells show that Cl⁻ and K⁺ facilitate acidification, with Cl⁻ possibly being the primary ion in some cases. The CLC family of Cl⁻ channels and transporters, including ClC-7, are candidates for the counterion pathway. ClC-7 is localized to lysosomes and is involved in maintaining lysosomal pH, though knockout studies show conflicting results. The role of ClC-7 in lysosomal acidification remains debated. Other transporters, such as TRPML1, may also contribute to cation transport. The V-ATPase is the primary driver of acidification, converting metabolic energy into proton gradients. The mechanisms of counterion movement and their role in lysosomal pH regulation are still not fully understood, with new research suggesting dynamic regulation of lysosomal pH. Future studies aim to clarify the roles of V-ATPase isoforms, the contributions of anion and cation transport, and the molecular basis of lysosomal cation permeability.Lysosomes are terminal organelles in the endocytic pathway that digest macromolecules and release their components as nutrients. They maintain a highly acidic pH (4.5-5.0) through the activity of a V-type ATPase, which uses ATP to pump protons into the lysosome lumen. This process generates a transmembrane voltage, requiring the movement of a counterion (either a cation or anion) to dissipate the voltage and allow net proton transport. Recent studies suggest that ClC-7, a Cl⁻/H⁺ antiporter, may be involved in this process, though its exact role remains unclear. The V-ATPase is electrogenic, generating a voltage that must be dissipated by counterion movement. The counterion pathway is crucial for maintaining lysosomal pH, with anion and cation permeabilities both contributing. Studies in isolated lysosomes and intact cells show that Cl⁻ and K⁺ facilitate acidification, with Cl⁻ possibly being the primary ion in some cases. The CLC family of Cl⁻ channels and transporters, including ClC-7, are candidates for the counterion pathway. ClC-7 is localized to lysosomes and is involved in maintaining lysosomal pH, though knockout studies show conflicting results. The role of ClC-7 in lysosomal acidification remains debated. Other transporters, such as TRPML1, may also contribute to cation transport. The V-ATPase is the primary driver of acidification, converting metabolic energy into proton gradients. The mechanisms of counterion movement and their role in lysosomal pH regulation are still not fully understood, with new research suggesting dynamic regulation of lysosomal pH. Future studies aim to clarify the roles of V-ATPase isoforms, the contributions of anion and cation transport, and the molecular basis of lysosomal cation permeability.