The precise and coordinated production of myelin is essential for proper development and function of the nervous system. Diseases that disrupt myelin, including multiple sclerosis, cause significant functional disability. Current treatment aims to reduce the inflammatory component of the disease, thereby preventing damage resulting from demyelination. However, therapies are not yet available to improve natural repair processes after damage has already occurred. A thorough understanding of the signaling mechanisms that regulate myelin generation will improve our ability to enhance repair. in this review, we summarize the positive and negative regulators of myelination, focusing primarily on central nervous system myelination. Axon-derived signals, extracellular signals from both diffusible factors and the extracellular matrix, and intracellular signaling pathways within myelinating oligodendrocytes are discussed. Much is known about the positive regulators that drive myelination, while less is known about the negative regulators that shift active myelination to myelin maintenance at the appropriate time. Therefore, we also provide new data on potential negative regulators of CNS myelination. The precise and coordinated production of myelin is essential for proper development and function of the nervous system. Diseases that disrupt myelin, including multiple sclerosis, cause significant functional disability. Current treatment aims to reduce the inflammatory component of the disease, preventing damage damage from from However, therapies are not yet available to improve natural repair processes after damage already occurred. A thorough understanding of the signaling mechanisms that regulate myelin generation will improve improve ability to enhance repair. in this review, we summarize the positive and negative regulators. of myelination, focusing on on central nervous system myelination. Axon-derived signals, extracellular signals from both diffusible factors and the extracellular matrix, and intracellular signaling pathways within my nervous oligodendrocytes are discussed. Much is known about the positive regulators that drive myelination, while less is known about the negative regulators that shift active myelination to myelin maintenance at the appropriate time. Therefore, we also provide new data on potential negative regulators of CNS myelination.