ALTHOUGH THE US FOOD AND DRUG ADMINISTRAtion (FDA) reviews and approves drugs for specific indications, the approval does not usually limit the use of those drugs in clinical practice. Indeed, prescribing for indications not reviewed by the FDA (“off-label”) is common. In a recent study of 160 frequently prescribed drugs, off-label use represented 21% of drug mentions, and 73% of these off-label uses had little or no scientific support. Off-label use has long been controversial because large numbers of patients may receive drugs that have had only limited testing for efficacy and safety, and some off-label uses may eventually be shown to have an unfavorable risk-benefit profile. High-profile examples include the use of the combination of fenfluramine and phentermine by millions of persons for weight loss and the widespread use of hormone therapy by postmenopausal women to prevent coronary artery disease. Although the FDA does not restrict physician prescribing for off-label indications, it does regulate the manufacturer’s promotion for such use. The FDA Modernization Act of 1997 permitted sponsors to disseminate peer-reviewed studies from scientific journals about off-label uses that had been or would form part of a supplementary New Drug Application (sNDA). These provisions expired in September 2006 with the result that current law prohibits any promotion of a drug for unapproved uses. Recently, the FDA proposed new guidelines that enable sponsors to distribute publications about unapproved uses of approved drugs and devices. For drugs, for example, an sNDA is no longer required. The journal that published the article to be distributed must have both an editorial board that uses independent reviewers and a policy of full disclosure of conflict of interest; the article must be peer-reviewed; and the article should not be in a supplement funded by the sponsor. The information should address adequate and well-controlled clinical investigations and not be false, misleading, or pose a significant threat to health. Distribution is to include the product label, a relevant bibliography, and a representative publication, if it exists, that reaches a different conclusion about the unapproved use. Are these proposed changes consistent with the FDA’s mission of protecting the public health by ensuring the efficacy and safety of medications? Although peer-reviewed literature serves as the gold standard for evidence-based medicine, there are major limitations in relying on sponsordistributed literature to regulate off-label use, including the selective publication of studies, the systematic manipulation of the literature, the absence from the literature of critical data necessary for evaluating off-label use, and the potential for undermining the NDA review process.