Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Healthcare systems are challenged with implementing high-cost, high-impact medication therapies with increasing frequency. Pharmacy & therapeutics (P&T) committees may struggle to integrate requests for these medications into their existing formulary review process. This article describes one large academic medical center’s experience with creating a new P&T subcommittee that addresses the clinical, operational, and financial challenges these medications present. Summary The High-Impact Medication Therapy Subcommittee was established to optimize the institution’s process for reviewing formulary requests for medications that are defined as “high impact”—nononcology medications that are extremely expensive and/or have complex operational or clinical challenges. The multidisciplinary subcommittee has 3 chairs—a physician, a nurse, and a pharmacist—and includes representation from all areas of pharmacy practice (clinical pharmacy, operations, supply chain, finance, and informatics), as well as medical and nursing leadership, hospital finance, and patient access services. Additional relevant stakeholders are invited as needed. The first medication to be reviewed at this subcommittee was afamelanotide, a melanocortin receptor agonist indicated for treatment of erythropoietic protoporphyria. The subcommittee addressed cost-efficacy concerns and operational challenges, and the final recommendation was for formulary addition, with clearly defined restriction criteria and the creation of a new workflow to meet the unique operational considerations with this drug. Conclusion As medication costs continue to rise at unprecedented rates and reimbursement requirements continue to increase in complexity, the High-Impact Medication Therapy Subcommittee provides a necessary venue for reviewing high-cost medications with complex clinical or operational considerations and proactively addressing implementation challenges.