Polypharmacy, defined as regular use of at least five medications, is common in older adults and younger at-risk populations and increases the risk of adverse medical outcomes. There are several risk factors that can lead to polypharmacy. Patient-related factors include having multiple medical conditions managed by multiple subspecialist physicians, having chronic mental health conditions, and residing in a long-term care facility. Systems-level factors include poorly updated medical records, automated refill services, and prescribing to meet disease-specific quality metrics. Tools that help identify potentially inappropriate medication use include the Beers, STOPP (screening tool of older people's prescriptions), and START (screening tool to alert to right treatment) criteria, and the Medication Appropriateness Index. No one tool or strategy has been shown to be superior in improving patient-related outcomes and decreasing polypharmacy risks. Monitoring patients' active medication lists and deprescribing any unnecessary medications are recommended to reduce pill burden, the risks of adverse drug events, and financial hardship. Physicians should view deprescribing as a therapeutic intervention similar to initiating clinically appropriate therapy. When deprescribing, physicians should consider patient/ caregiver perspectives on goals of therapy, including views on medications and chronic conditions and preferences and priorities regarding prescribing to slow disease progression, prevent health decline, and address symptoms. Point-of-care tools can aid physicians in deprescribing and help patients understand the need to decrease medication burden to reduce the risks of polypharmacy.