Adult-onset leukodystrophies are clinically and pathologically heterogeneous diseases, and the overlapping morphologic features among these disorders can lead to confusion in pathologic classification. We report 3 recent autopsy cases that illustrate the clinicopathologic distinction between the 3 entities. The first, autosomal dominant leukodystrophy, is characterized clinically by early autonomic dysfunction and genetically by LMNB1 (lamin B1 gene) duplication. Recently, another clinical subtype emerged without the early autonomic dysfunction but with a similar genetic abnormality documented in 1 family. We reviewed the reported autopsy cases and show that both clinical subtypes share distinctive pathologic features. Other forms of adult-onset leukodystrophy can be classified based on the histologic evidence of the primary pathologic processes. A case of axonopathy with secondary demyelination serves as a prototype for adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids; the genetic mutation of CSF1R (colony stimulating factor 1R) was recently discovered in patients with this disorder. A case of a primary demyelinating disease with no other distinctive pathologic features is designated as orthochromatic leukodystrophy. Pigmented glia can be present in both of the latter two categories and should not be used as a differentiating diagnostic feature. Based on the observations of our cases and literature review, we propose an algorithm for a practical diagnostic approach to adult-onset leukodystrophies.