Next-generation sequencing (NGS) is increasingly being applied to clinical testing. This practice is predicted to grow especially in neurology clinics because many of their patients have monogenetic causes for their “diagnostic odyssey.” The cost of sequencing has been steadily decreasing, but the cost of DNA sequencing is a minor part of the total cost. Downstream data analysis, storage, and interpretation account for most of the total expense. In patients with nonspecific neurologic disorders in which an extensive number of genetic differential diagnoses exist, whole-genome sequencing (WGS) or whole-exome sequencing (WES) has shown promise in the identification of genetic causes. However, both WGS and WES have incomplete coverage and produce a large number of rare variants of unknown importance. In addition, ethical dilemmas are often created by unexpected findings in genes unrelated to the initial sequencing indication. Targeted-panel NGS starts with the capture of a set of disease-focused genes, followed by massive parallel sequencing. For many genetically heterogeneous neurologic disorders, a genetic panel that is disease focused yet inclusive of a large genetic differential diagnosis can be defined to reduce cost, increase turnaround time, and optimize performance. Targeted-panel NGS is currently the preferred first-tier approach because it provides a reliable clinical application while eliminating unexpected ethical dilemmas. Targeted-panel NGS is leading to a paradigm shift in the diagnosis of many neurologic disorders, enabling individualized precision medicine. In this review, we provide an overview of WGS, WES, and targeted-panel NGS in consideration of their utility in clinical testing for neurologic diseases.