Prescribing medications safely and effectively in older adults is a complex process. This review discusses challenges with medication prescribing in older adults and outlines a holistic approach to medication management in older adults. Well-known challenges including the alterations in pharmacokinetics and pharmacodynamics that often occur with aging are discussed. Other classic concerns including polypharmacy, potentially inappropriate medication use, prescribing cascades, suboptimal prescribing, paradoxical harm and unintended consequences of medications, and drug interactions are reviewed. Newer approaches, including deprescribing, pharmacogenomics, and the future potential for senolytic therapy are also discussed. All healthcare providers should consider these challenges when prescribing medications in older adults. Choosing a drug that fits both a patient's pathophysiology and biology, avoiding drugs with significant side effects, titrating doses, and deprescribing are all critical in optimizing medication therapy.