Autophagy is a lysosomal degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and protein aggregates. These substrates reach lysosomes by several distinct mechanisms, including delivery within endosomes as well as autophagosomes. Completion of digestion involves dynamic interactions among compartments of the autophagic and endocytic pathways. Neurons are particularly vulnerable to disruptions of these interactions, especially as the brain ages. Not surprisingly, mutations of genes regulating autophagy cause neurodegenerative diseases across the age spectrum with exceptional frequency. In late-onset disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and familial Parkinson's disease, defects arise at different stages of the autophagy pathway and have different implications for pathogenesis and therapy. This Review provides an overview of the role of autophagy in neurodegenerative disease, focusing particularly on less frequently considered lysosomal clearance mechanisms and their considerable impact on disease. Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated.