Focal symmetric demyelination in the central nervous system may be precipitated by aggressive correction of a hyper- or hypo-osmolar state and until recently has been associated with a high rate of morbidity and mortality. Specific anatomical locations are more susceptible to demyelination than others, although the mechanism of injury is unknown. Classic clinical and anatomical descriptions associated with a central pontine location have been supplemented by descriptions of patients with unusual symptoms associated with demyelinating lesions in extrapontine locations. The separation of patients with myelinolysis in central pontine and extrapontine locations is possible on the basis of clinical symptoms, and may direct specific pharmacological treatment. Patients at risk of central myelinolysis who are subjected to aggressive osmolar correction may be rescued with appropriate fluid management before brain injury has occurred; once injury is suspected on the basis of neurological symptoms, additional forms of intervention may still improve the outcome. Recent investigation of the molecular basis of the demyelinating process and the adaptive responses of the brain to dysosmolar challenge has allowed for the refinement of standard treatments and has made the osmotic demyelination syndrome a treatable condition with a better than expected prognosis.