Older adults often have co-occurring multiple chronic and acute diseases, which progressively and steadily increase in prevalence with age (1, 2). The treatment of these diseases usually requires multiple drugs (polypharmacy); it has been estimated that more than 50% of persons aged 65 years or older receive five or more drugs concomitantly (3, 4). Drug use in the older population might raise several concerns related to an increased risk of drug-drug and drug-disease interactions, poor adherence to treatment, and increased risk of adverse drug reactions (5-7). In this chapter we will discuss what role drugs and polypharmacy play in the development, management and treatment of frailty.