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Axons are the major output processes of neurons, responsible for transmitting information to other neurons and tissues throughout the body. The 150,000+ kilometers of axons make up half of the brain's volume and require a large amount of energy. Normal axon function is the product of a massive number of intra- and extra-cellular mechanisms working in concert. Perhaps not surprisingly, the axon is a site of vulnerability during normal aging and in disease states, although this has only been recently appreciated. Axonopathy, broadly defined as functional or structural defects in the axon or its terminal, is common across a wide range of neurodegenerative conditions, including amyotrophic lateral sclerosis, Huntington’s, Parkinson’s, and Alzheimer’s diseases, glaucoma, and as a result of neurotoxin exposure or drug treatment. This Research Topic assembles a series of original research papers, reviews, and commentaries that will illustrate both the commonalities and important differences across neurodegenerative disorders. Though this collection cannot address all aspects of this topic, it is our hope that these manuscripts will educate other scientists and inspire new investigations into axon dysfunction and degeneration.