“Off-label use” occurs when the use of a medication or device deviates from what is mentioned in its US Food and Drug Administration (FDA) product label. Off-label use is common, legal, and an important source of innovation; however, it can be costly, and strong evidence of the efficacy and safety of such use may be lacking.1 Given the contradictory and unresolved expectations of major stakeholders, off-label use remains problematic. It requires a new policy paradigm that can successfully balance the need for innovation against the imperatives of evidence-based practice and finite health-care resources. Clinical Pharmacology & Therapeutics (2012); 91 5, 920–925. doi:10.1038/clpt.2012.22