Polypharmacy is a problem of growing interest in geriatrics with the increase in drug consumption in recent years, particularly among people aged >65 years. The main reasons for polypharmacy are longer life expectancy, co-morbidity and the implementation of evidence-based clinical practice guidelines. However, polypharmacy also has important negative consequences, such as a higher risk of adverse drug reactions and a decline in medication efficacy because of reduced compliance. Comprehensive geriatric assessment (CGA) has proved effective in reducing the number of prescriptions and daily drug doses for patients by facilitating discontinuation of unnecessary or inappropriate medications. CGA has also demonstrated an ability to optimize treatment by increasing the number of drugs taken in cases where under-treatment has been identified. Greater multidimensional and multidisciplinary efforts are nonetheless needed to tackle polypharmacy-related problems in frail elderly patients. CGA should help geriatrics staff identify diseases with higher priority for treatment, thereby achieving better pharmacological treatment overall in elderly patients. The patient's prognosis should also be considered in the treatment prioritization process. The most appropriate medication regimen should combine existing evidence-based clinical practice guidelines with data gathered from CGA, including social and economic considerations. Furthermore, for prescriptions to remain appropriate, the elderly should periodically undergo medication review, particularly as the risk or presence of multiple co-morbidities increases. This article aims to highlight the increasing impact of polypharmacy in the elderly and to underscore the role of CGA in achieving the most appropriate pharmacological treatment in this age group.