Neurological disorders secondary to single gene mutations are an extremely heterogeneous group of diseases, individually rare, and often associated with progressive and severe disability. Given the degree of both clinical and genetic heterogeneity, next-generation sequencing (NGS) has become an important diagnostic tool. Multi-gene panel testing based on NGS is now prominently used, while whole-exome sequencing and whole-genome sequencing are emerging to facilitate the molecular diagnosis for many genetic neurological diseases. Although single-gene testing remains an important first tier test for disorders with clear phenotype-genotype correlation, NGS provides an expanding unbiased approach to identify rare mutations in genes known to be associated with genetically heterogeneous diseases, and those not initially considered by the clinician due to rarity or atypical clinical presentation. Given the decreasing costs and relatively rapid time to results, NGS-based assessment is quickly becoming a standard-of-care test for patients with genetic neurological diseases.