Polypharmacy refers to the prescribing of many medicines for one individual. Polypharmacy is increasingly common as a result of the rise in multimorbidity, use of evidence-based clinical guidelines and care pathways, and a focus on disease prevention. Polypharmacy can be justified and appropriate, but it may also be inappropriate and associated with suboptimal health outcomes and mortality. Polypharmacy is associated with adverse drug events such as drug-drug interactions and adverse drug reactions (ADRs). Taking multiple medicines can adversely affect adherence, resulting in lost opportunities for health gain and wasted medicines. Older people, and particularly those who are frail, are susceptible to the adverse effects of polypharmacy. Medication reviews should be undertaken regularly in older people with polypharmacy. Medicines management systems, research, and education are essential to improve safe practice in the management of polypharmacy.