The leukodystrophies are inherited disorders of brain white matter that are often associated with cognitive impairment. Although most classically affected individuals present in childhood, there are late-onset cases wherein the diagnosis is often missed, particularly in the absence of a family history. Although cognitive and behavioral changes can be a presenting complaint and may arise at any stage, these problems are rarely the only manifestations. Leukodystrophies usually follow a slowly progressive course, rather than a relapsing–remitting one. Spasticity, motor weakness, and ataxia are common features, and the presence of peripheral neuropathy and/or autonomic dysfunction may be a valuable clue in the differential diagnoses. Biochemical and/or molecular confirmatory testing is available for a selected group of leukodystrophies, which should be distinguished from cases of multiple sclerosis, so patients are given proper counseling and treatment. Unfortunately, management of leukodystrophies is largely symptomatic, although a genetic diagnosis enables appropriate counseling regarding prognosis and reproductive risks, if applicable, and the provision of treatment, if available.