Polypharmacy is the concurrent use of five or more drugs per day. It is common in old age because of multimorbidity. The prevalence of polypharmacy is increasing as the number of old people is increasing worldwide. The proliferation of clinical guidelines and wider availability of preventive and curative medicines are important causes of polypharmacy. Appropriate polypharmacy is beneficial to the patients. However, polypharmacy may be inappropriate, causing adverse effects, drug interactions (DI), poor treatment efficacy, hospitalizations, and high healthcare costs. Prescribing cascade and legacy prescribing add to the burden of inappropriate polypharmacy. Inappropriate polypharmacy can be prevented or managed by medication optimization through medication review, deprescription, ensuring adherence, and patient education. Deprescription includes the removal of risky, unnecessary, and duplicate drugs, replacement with efficacious drugs, and relaxation of tight control as per life expectancy. Several deprescription tools (both explicit and implicit) exist for helping physicians to decide when to deprescribe or to add medicines, especially in old age. Care should be taken during deprescription to prevent unjustified omission, reduction to subtherapeutic dose, and onset of withdrawal features. Age and disease-related changes in pharmacokinetics and pharmacodynamics of drugs should be considered during the optimization of pharmacotherapy.