Myelin is a highly specialized membrane, which wraps around nerve fibers in the peripheral (PNS) and central (CNS) nervous systems and is required for rapid conduction of nerve impulses. Myelin formation is tightly regulated and while the molecular events controlling the formation of Schwann cells (SC) and oligodendrocytes (OL), the glial cells responsible for making myelin, have been characterized, the axonal mechanisms directing its production have been only recently identified. Studies from our laboratory have focused on defining the signals on the axon, and the downstream signaling pathways they activate in myelination. These signals are important to regulate the generation and formation of glial cells and ultimately, maintenance of the myelin sheath. We have recently showed that type III NRG1, a member of the Neuregulin1 (NRG1) family of proteins, is as an essential instructive signal for myelination in the PNS and promotes myelination in the CNS. We are now investigating how type III NRG1 is expressed on the axon and the regulation of the signal transduction pathway activated in glial cells during myelination. The identification of the neuronal proteins involved in regulating myelination are likely to provide important insights into the mechanisms required for its generation and maintenance and could be effective to develop therapies for demyelinating diseases in which the disability is correlated to myelin and axonal loss.