The leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Leukodystrophies are a group of approximately 30 genetic diseases that primarily affect the white matter of the central nervous system (CNS) and remain a diagnostic challenge for clinicians and researchers. As a whole, leukodystrophies are relatively common (approximately 1 in 7000 births). This genetically heterogeneous set of disorders is categorized based on initial findings of white matter abnormalities in the CNS. Historically, these abnormalities were identified using gross pathology. More recently, neuroimagery has been used for diagnostic purposes. However, more than half of the suspected leukodystrophies do not have a definitive diagnosis, and are classified as "leukodystrophies of unknown etiology". Even when a diagnosis is achieved, the diagnostic process lasts an average of eight years and results in test expenses in excess of $8,000 on average per patient, including the majority of patients who never achieve a diagnosis at all. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients. The diagnostic workup begins with findings on cranial Magnetic Resonance Imaging (MRI) followed by sequential targeted genetic testing, however next generation sequencing technologies (NGS) offer the promise of rapid and more cost effective approaches. In general, NGS has the potential to revolutionize medical research and diagnostics, particularly for rare diseases - 80% of which are genetic in origin. In the last two years, the pace of discovery has increased at a remarkable rate due to the use of whole genome sequencing (WGS) and whole exome sequencing (WES). Recent reports suggest that WES can yield insights into previously ambiguous rare genetic disorders. For example, large-scale WES projects have been used to identify new nosologic entities using clinical and molecular data in adult onset leukodystrophy, neurodevelopmental disorders, epilepsy/ epileptic encephalopathies, degenerative ataxia, and intellectual disability. In clinical settings, WES has also been shown to provide diagnoses for atypical presentations of established disorders. Overall, diagnostic yields for large disease cohorts range from 16-53%.