Adult, circuit-integrated, neurons must be maintained and supported for the life span of their host. The attenuation of either maintenance or plasticity leads to impaired circuit function and ultimately to neurodegenerative disorders. Over the last few years, significant discoveries of molecular mechanisms were made that mediate the formation and maintenance of axons. Here, we highlight intrinsic and extrinsic mechanisms that ensure the health and survival of axons. We also briefly discuss examples of mutations associated with impaired axonal maintenance identified in specific neurological conditions. A better understanding of these mechanisms will therefore help to define targets for therapeutic interventions.