Physicians commonly prescribe Food and Drug Administration–approved drugs for off-label indications. Although some off-label uses are standard of care, many others have little or no scientific support. Few guidelines regarding the assessment of evidence or consent for off-label use are available to physicians. In this article, the authors identify 4 drug characteristics that signal the need for rigorous scrutiny of evidence before off-label prescribing: new drugs, novel off-label indications, serious adverse effects, and high cost. For off-label uses characterized by 1 or more of these signals for scrutiny, an evidence-guided ethical framework distinguishes 3 potentially appropriate categories of off-label use: (1) supported off-label use, (2) suppositional off-label use, and (3) investigational off-label use. These categories are based on the validity and relevance of available evidence. The categories are then linked to specific requirements for appropriate off-label prescribing, including the nature of disclosure to patients of the risks and benefits involved.