This article challenges the scope of physician discretion to engage in off-label use of prescription drugs. The discretion to prescribe dimensions beyond the clinical research that puts new drugs on pharmacy shelves has been shaped by two historic influences: a legacy of physician paternalism, solidarity, autonomy, and self-determination that predates the contemporary commercialization of medicine by more than half a century, and regulatory necessity due to the limits of science and innate crudeness of pharmaceuticals prior to the genomics revolution (drug development and delivery based upon genetic expression). Although both factors have changed immensely, the standard for drug approval has lingered. This article proposes that doctor discretion to prescribe off label must be modified and the regulatory standard for new drug approvals raised given the proliferation of adverse events, drug ineffectiveness, the need to make choices among treatment options under time pressures, the increasing complexity of biopharmaceuticals, health care cost pressures, and the vulnerability of patients—seekers of health care, not research subjects protected under the scrutiny of regulations to protect human subjects. The article concludes that, although some physician discretion to prescribe off label still is necessary, law-policy reforms to shift more of the drug discovery process from the clinical care of patients to clinical research in drug development are long overdue. Proposals to accomplish this, drawn from recent legislation and ongoing health care reform, include heightening the regulatory standards for new drug approvals and drug reimbursement.