Neurological diseases of the central nervous system (CNS) represent a growing global health burden, particularly in older adults, where age-related changes in brain structure, vascular function, and cellular resilience exacerbate disease susceptibility. Conditions such as Alzheimer’s disease, Parkinson’s disease, stroke, and epilepsy are increasingly prevalent with aging, contributing substantially to disability-adjusted life years (DALYs) worldwide. Pharmacogenomics (PGx) has emerged as a promising tool to optimize CNS pharmacotherapy by tailoring treatments to individual genetic profiles, aiming to enhance efficacy and reduce adverse drug reactions. Key actionable pharmacogenomic markers—such as CYP2C19, CYP2D6, and CYP2B6—influence the metabolism of CNS medications including antidepressants and antipsychotics, although the clinical utility of additional biomarkers remains limited by insufficient evidence. Despite its promise, implementing PGx in older adults poses unique challenges, including polypharmacy, altered pharmacokinetics, pharmacodynamics, and complexities surrounding blood–brain barrier penetration. This chapter explores the integration of PGx into CNS pharmacotherapy in older adults, emphasizing both its potential benefits and the limitations in translating genetic insights into routine clinical practice to improve neurological outcomes in an aging population.