Abstract: Integrity of the plasma membrane is essential for the maintenance of physiological conditions, metabolic activity and the shape of eukaryotic cells. In neurons, the plasma membrane surrounding the axon—the axolemma—fulfills all these functions plus those inherent to the specific function of the neuron: maintaining the membrane potential by the regulated and concerted operation of ion-selective channels. Membrane expansion and neurite growth are directly linked through intricate cellular signaling mechanisms during the early stages of embryonic development. During axonal development there is an increase in the surface area of the axolemma which provokes an increase in membrane tension. Membrane insertion involved in axonal growth reduces the membrane tension, and this in turn allows distal membrane expansion and axonal extension. Under certain pathological conditions, such as spinal cord and traumatic brain injuries, the axolemmal damage results in different degrees of neuronal degeneration due to unregulated ionic influx, followed by oxidative damage, finally triggering neuronal apoptosis. Neurons possess counteractive mechanisms to arrest these degenerative processes which involve sealing the axolemma as a first step toward membrane repair, followed by attempts at axonal extension. In this review we address the main molecular actors and mechanisms involved in axonal growth during embryonic development and the recapitulation of these mechanisms during the posttraumatic regeneration process. We also discuss the efficacy of some classical and novel therapeutic approaches to axolemmal sealing and repair in different pathologies.