Polypharmacy is a commonly addressed problem in the elderly. It is the use of a minimum of four medicines simultaneously. However, the elderly population suffers not only from the overuse of the medicines but also from the underuse. Furthermore, not uncommonly, use of a minimum of four medicines designated as polypharmacy, may be rational in many clinical circumstances in the elderly. In this article, we review the principles of rational drug use in the elderly. The main aim of the geriatric management increasing the quality of life should also be the purpose of the drug therapy. The physiological changes that occur by aging should be taken into account. The patient or caregiver should be informed on the drug list, instruction on use, possible side effects and indication of the current regimen. The drugs taken by the patient should be checked against the recommended regimen. The regimen should be reviewed for indication, appropriateness and possible switch to a safer or cheaper agent, minimum effective dosage, timing, effectiveness, side effects and toxicity, and potential drug-drug interaction one by one. This checking should be performed in a periodical manner and also in any acute deterioration. The potentially useful drugs should not be underused. This approach may decrease both the overuse and underuse of medicines resulting in the rational drug use of the vulnerable elderly.