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Polypharmacy presents a major challenge when caring for older adults and increasingly causes preventable health problems in both inpatient and outpatient settings. While it is often defined as taking five or more medications, it is more accurately seen as a clinical condition where medication burden surpasses physiological capacity, is unnecessary, or is incongruent with patient-centered goals. Age-related changes in drug absorption, distribution, metabolism, and excretion, along with multiple chronic conditions, fragmented care, and frequent transfers between healthcare environments, create a perfect storm for medication-related adverse effects. Falls, syncope, confusion, fatigue, low blood pressure, slow heart rate, or functional decline can be mistaken for evidence of underlying illness rather than side effects of medication. Medication reconciliation can therefore serve as a powerful diagnostic, therapeutic, and safety measure to avoid the harmful effects of polypharmacy. This review offers a practical, detailed, step-by-step approach to managing polypharmacy for internists, with a particular focus on medication reconciliation in older adults.