Axons are long, thin, and critically important for neuronal communication in the body. When an axon is damaged, it undergoes a stereotyped set of molecular and cellular changes resulting in its fragmentation and loss, destroying its connection with target cells. In the central nervous system, axons are unable to regenerate, while in the peripheral nervous system, the process is slow and often painful. Importantly, while many types of insults trigger axon degeneration, the molecules activated by these insults are often the same. By understanding the initiation and execution of the basic process of axon degeneration, we have an opportunity to impact the treatment of many neurodegenerative diseases ranging from diabetic neuropathy to Alzheimer's Disease.