The lysosome is the main catabolic hub of the cell. Owing to its role in fundamental processes such as cellular catabolic reactions, membrane repair, and cell death, the lysosome has a profound influence on cellular metabolism and human health. Indeed, inefficient or impaired lysosomal function has been implicated in the pathogenesis of several degenerative diseases affecting various organs and tissues. This special issue presents five review articles stemming from the conference \"Drugs Targeting the Lysosome,\" sponsored by the New York Academy of Sciences and Beyond Batten Disease Foundation in November 2014. The articles discuss recent discoveries in lysosome biology and the therapeutic potential of drugs targeting the lysosome in various diseases. The specific topics covered include the potential of TFEB as a therapeutic target for the treatment of lysosomal storage diseases (LSDs); LSD-relevant cellular and animal models with high clinical predictability; the contributions of lysosomal membrane permeabilization to the pathogenic features of LSDs and other neurodegenerative conditions; the therapeutic potential of drugs targeting the lysosome in cancer and the role of lysosomes in cancer drug resistance; and current understanding of vision loss in juvenile neuronal ceroid lipofuscinosis.