Advances in biochemical techniques, molecular genetics, and neuroimaging, particularly magnetic resonance imaging, have made possible the diagnosis of a significant proportion of leukodystrophies. A specific diagnosis allows the physician to give prognostic information, monitor for known complications, and ultimately may allow disease specific therapeutics. The purpose of this review is to familiarize the reader with pertinent tools in the diagnosis of leukodystrophies and other white matter disorders that may present with white matter disease. The first section discusses conditions that may mimic leukodystrophy and how to exclude them. Although not meant to be an exhaustive summary, several key disorders and their clinical, biochemical, and neuroimaging features are presented. The second section focuses on classically described leukodystrophies and their diagnosis. Finally, a third section provides a diagnostic algorithm to help the clinician in the diagnosis of the patient with leukodystrophy.