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Purpose of Review: We provide a review of considerations when applying principles of optimal pharmacotherapy to older adults with heart failure (HF), an analysis on the pivotal clinical trials focusing on applicability to older adults, and multi-disciplinary strategies to optimize the health of HF patients with polypharmacy., Recent Findings: Polypharmacy is very common among patients with HF, due to medications for both HF and non-HF comorbidities. Definitions of polypharmacy were not developed specifically for older adults with HF and may need to be modified in order to meaningfully describe medication burden and promote appropriate medical therapy. This is because clinical practice guidelines for multi-drug HF regimens have unique considerations, given that they improve outcomes and symptoms of HF. Adults older than 65 years are well represented in contemporary clinical trials for HF with preserved ejection fraction (HFpEF) and guideline directed medical therapy (GDMT) for HF with reduced ejection fraction (HFrEF). While these trials did not have significant heterogeneity in safety or efficacy across a broad age spectrum, some may have limited representation of adults ≥ 80 years old, the sickest older adults, or those with decreased functional status. There is also a lack of data on the safety and efficacy of deprescribing HF medications, and deprescription in otherwise stable patients may lead to clinical destabilization or disease progression. There is therefore innate tension between the well-studied benefits of optimized HF therapy for older adults that must be weighed against the risks of polypharmacy and many unknowns that still exist. Given the strong evidence that optimized HF therapies confer symptomatic and mortality benefits for older adults, it is clear that polypharmacy in this context can be appropriate. A shift in paradigm is therefore needed when evaluating polypharmacy in patients with HF. Instead of assuming all polypharmacy is "good" or "bad," we propose a concerted move, using a multidisciplinary approach, to focus on the "appropriateness" of specific medications, in order to optimize HF medical therapy. Clinicians of all specialties caring for complex older adults with HF must consider goals of care, functional status, and new evidence-based therapies, in order to optimize this polypharmacy for older adults., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)