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After an impressively successful application as a research instrument, whole-exome sequencing (WES) now enters the clinical practice due to its high diagnostic, time, and economic efficiency. WES is the diagnostic method of choice for symptoms that may be due to many different monogenic causes. Neurological indications include movement disorders, especially in cases of early symptom onset, familial clustering and complex manifestation. Starting from a blood sample, enrichment and sequencing of the exome enable the examination of all coding DNA regions for point mutations and small insertions/deletions. The identification of variants as the cause of a disease requires a professional evaluation pipeline, variant prioritization schemes and variant classification databases. Whereas many variants can be reliably classified as pathogenic or benign, variants of unclear significance (VUS) remain a challenge for the clinical evaluation and necessitate a periodic reanalysis of WES data. As a genetic examination WES requires adequate patient informed consent which in particular should address possible secondary findings as well as data security. A positive molecular result ends diagnostic odysseys, enables accurate genetic counseling and can point to targeted preventive measures and treatment. A WES significantly contributes to the understanding of the genetic architecture and pathophysiology of neurological diseases, enriching and enabling precision medicine.