Heart failure (HF) is predominantly a disease that affects the elderly population, a cohort in which comorbidities are common. The majority of comorbidities and the degree of their severity have prognostic implications in HF. Polypharmacy in HF is common, has increased throughout the past 2 decades, and may pose a risk for adverse drug interactions, accidental overdosing, or medication nonadherence. Polypharmacy, in particular in the elderly, is rarely assessed in traditional clinical trials, highlighting a need for entirely novel HF research strategies.