The lysosome has emerged over the past decade as a key-signalling hub within the cell, in addition to its better-known role in macromolecule catabolism and recycling. Lysosomal dysfunction leads to devastating human diseases, the best characterised of which are the rare monogenic diseases, the lysosomal storage diseases (LSDs). However, we have recently begun to appreciate that lysosomal dysfunction occurs in a much broader range of rare and common human diseases and may represent a novel therapeutic target.