Medication-related disability, due to a severe adverse drug reaction (ADR) causing significant functional impairment, represents a major public health challenge. This entry provides a comprehensive overview of this form of iatrogenic harm, exploring its identification, burden, and management. It begins by detailing causality assessment frameworks used to link drugs to adverse events. The discussion then quantifies the substantial epidemiological and economic burden of ADRs, which are a leading cause of hospitalization, and explores their profound impact on patients’ quality of life. This entry also examines the diverse clinical manifestations, from neurological disorders to severe systemic syndromes. It delves into the underlying mechanisms, highlighting key risk factors including polypharmacy, age-related physiological changes, and pharmacogenomic predispositions. A multi-layered strategy for mitigation is presented, encompassing pharmacovigilance, structured medication reviews, deprescribing, and patient-centered rehabilitation. Finally, this entry analyzes the critical ethical, legal, and policy dimensions that frame professional responsibility and patient safety. Overall, a systematic, proactive approach is essential to minimize preventable medication-related harm, safeguard patient well-being, and uphold the fundamental principles of medical practice.