Development and maintenance of PNS myelin depends on continual signaling from axons ensheathed by myelin. Recent advances have demonstrated the roles of neuregulin 1 type III, Erb2/3 and intracellular signal transduction pathways in inducing Schwann cell myelination. Alternatively, maintenance of myelinated axons depends on healthy myelinating Schwann cells. Axonal degeneration is a feature of virtually all inherited demyelinating neuropathies and in many cases is more responsible for clinical impairment than the primary demyelination. Signaling mechanisms through which demyelinating Schwann cells damage axons are not well understood. In this review several examples of potential mechanisms by which demyelinating neuropathies damage axons will be presented. Understanding the molecular basis of Schwann cell-axonal interactions will not only increase the understanding of PNS biology but also identify therapeutic targets for inherited neuropathies.