Treating older patients is challenging. They present age-associated morphological and physiological changes; they have an increasing risk of frailty and multimorbidity and physical and cognitive functional deficits—all resulting in a higher vulnerability including a higher risk for adverse drug events (ADEs). ADEs are a frequent cause of avoidable hospital admissions in older patients. The single greatest predictor of ADEs is polypharmacy, the high number of medications that patients are being prescribed even in accordance with existing clinical guidelines for each of the multiple individual conditions diagnosed. These guidelines are usually for single conditions, they are not appropriate for older patients who often have multiple coexisting, mostly chronic conditions. They help drive polypharmacy by telling doctors when to start medications but not when to stop them. The scale of polypharmacy-related harm in the older patients is underestimated; it adds to the challenge of aging and avoidably drives the cost of the health-care system.