Central nervous system (CNS) disorders represent a major problem of health in developed countries, with important consequences in disability and health economics. Recent findings in CNS genomics and pharmacogenomics suggest that the introduction of pharmacogenomic procedures in clinical practice may help to optimize therapeutics (efficacy and safety issues). The genes involved in the pharmacogenomics of CNS drugs fall into five categories: (i) genes associated with CNS pathogenesis; (ii) genes associated with the mechanism of action of drugs; (iii) genes associated with drug metabolism; (iv) genes associated with drug transporters; and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions. Pharmacogenomics accounts for 30–90% variability in pharmacokinetics and pharmacodynamics. Only 20–30% of the Caucasian population processes normally approximately 60% of the current drugs that are metabolized via CYP2D6, CYP2C9, and CYP2C19. Clinical pharmacogenomics may contribute to personalizing pharmacological treatment, predicting patient/drug-dose selection, minimizing drug interactions, increasing drug efficacy, and reducing unnecessary costs.