Normal functions of critical lysosomal ion channels are often disrupted due to either genetic defect or inhibition by accumulated cellular waste material, which in turn results in lysosomal functional deficiency, a trademark observation in a number of neurodegenerative diseases and metabolic disorders. Activation or inhibition of ion channels via small molecule agents can help restore lysosomal function, which can then better regulate critical downstream processes (including autophagic flux and resolution, exocytosis, plasma membrane repair, and lysosomal biogenesis) to provide therapeutic benefit to patients.