Robust activation of the neuronal lysosomal system and cellular pathways converging on the lysosome, such as the endocytic and autophagic pathways, are prominent neuropathological features of Alzheimer's disease. Disturbances of the neuronal endocytic pathway, which are one of the earliest known intracellular changes occurring in Alzheimer's disease and Down syndrome, provide insight into how beta-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal system dysfunction in inherited disorders is commonly associated with prominent neurological phenotypes and neurodegeneration. New studies now directly implicate lysosomal cathepsins as proteases capable of initiating, as well as executing, cell death programs. These and other studies support the view that the progressive alterations of lysosomal system function in Alzheimer's disease have broad relevance to the neurodegenerative processes occurring during the disease.