Polypharmacy in the elderly population increases the morbidity and mortality. There are many factors that lead to polypharmacy in the elderly. Pharmacokinetic and pharmacodynamic properties of the drugs alter in the elderly. The side effects and drug-drug interactions increase in this population. In this text, polypharmacy in the elderly and the principles of rational drug use are mentioned in details. Decreasing polypharmacy and taking into account the principles of rational drug use should be considered in order to manage safe and efficient drug therapy in the elderly.