SUMMARY Many of the 100 billion neurons in the human central nervous system require a protective and insulating coating called myelin to function properly. Loss or damage of this myelin coating underlies many neurological disorders and therefore regeneration of new myelin is an important part of improving health for patients with multiple sclerosis (MS), neuromyelitis optica (NMO), and other myelin diseases such as the pediatric leukodystrophies. Without myelin, certain nerve cells cannot properly conduct electrical impulses, leading to weakness, fatigue, loss of vision, cognitive decline, and physical incapacity. We have developed a novel regenerative approach to identify important new potential treatments for patients with myelin loss or dysfunction that is built upon our expertise in stem cell biology. Our overall goal is to utilize the in vitro mouse and human stem cell platforms that we have developed to define the central mechanisms responsible for preventing myelin development and function across the full range of myelin disorders. We seek to discover novel therapeutic interventions that can modulate the function or regeneration of oligodendrocytes and astrocytes to restore myelination and neurological function. For multiple sclerosis, we have already defined a central mechanism to stimulate myelin regeneration and identified potent small molecules that can reverse paralysis in mouse models of disease. Moving forward, we seek to leverage our innovative technologies and experience in multiple sclerosis to identify disease- and context-specific effectors of myelin dysfunction and provide the basis for new therapies.