Chronic diseases and their treatment represent one of the greatest challenges for global healthcare. Polypharmacy, the simultaneous use of multiple medications, is often necessary in older and multimorbid individuals, but frequently leads to adverse drug reactions. Unfortunately, there is no standardized definition of problematic pharmacotherapy, which is why the prevalence of polypharmacy varies greatly depending on the definition used. The following chapter presents the risks of inadequate polypharmaceutical therapy, improvement strategies, and the role of medication adherence in multimorbid and chronically ill patients.