The leukoencephalopathies encompass a heterogeneous group of disorders that involve the brain white matter. The cause may be acquired or inherited; in the latter case, mutations have been found in genes that encode protein components of the myelin membrane or enzymes implicated in the turnover of myelin. In patients with cognitive dysfunction and white matter lesions evident on MRI, analysis of the type, pattern, and distribution of lesions can enable a presumptive diagnosis, which can be confirmed by biochemical and/or molecular testing. The presence or absence of peripheral neuropathy and/or autonomic dysfunction can be a helpful clue in differentiating individual diagnoses. Often, patients may be suspected of having and being initially treated inappropriately for a case of primary or secondary progressive multiple sclerosis. In a significant number of patients, the diagnosis may not be made, even after an extensive search. Establishing the cause enables counseling regarding prognosis, family planning, monitoring for disease-related complications, and introducing therapy, when available.