Background and Purpose— The control of stroke risk factors remains challenging. The “polypill” concept represents a novel approach for reducing stroke and cardiovascular risk factors in the entire population. The polypill would include several components and be provided without prescription to all adults of a certain age. Results— A polypill aimed at lowering blood pressure and cholesterol levels is estimated to potentially reduce the risk of a first ischemic stroke by 53%; this would translate to about 400 000 fewer strokes each year in the United States alone. Recommending a polypill for the entire older adult population would, however, include many individuals without the multiple risk factors targeted by its components, putting them at risk for drug-related side effects and responsible for the costs of a medication from which they would not derive benefit. Additional arguments for and against the polypill approach are discussed. Conclusions— Only clinical trials can provide the evidence needed to determine the usefulness of the polypill approach. Issues related to defining the components of the polypill, evaluating the pharmacodynamics and pharmacokinetics of a multiple-component formulation, and establishing safety and cost-effectiveness when given to large populations, however, are not trivial.