Innovative off-label medication use (defined as prescribing with reasonable rationale for use, but insufficient evidence to allay safety, efficacy, and cost-effectiveness concerns, yet is not clinical research) is common practice and provides challenges to ensuring high-quality health care and patient safety. This article describes a strategy to promote policy and standardization of innovative off-label medication use, ensure oversight of patient safety, and prospectively assess efficacy. A multidisciplinary group developed a policy and process to regulate innovative off-label medication use that standardizes formulary review, maximizes peer expertise input, and minimizes institution liability by evaluating the effectiveness of use, promoting evidence-based practices, and ensuring ethical obligations to patients and society. This strategy has been implemented through institutional staff structure. The review process balances benefits/risks for biologically plausible therapy that lacks rigorous data support. The authors' strategy illustrates collaboration that enables a priori consideration for innovative off-label medication use while providing safety surveillance and outcomes monitoring.