Fractures are an important public health problem affecting patients of all ages. Although most fractures heal quickly, some heal poorly and some do not heal at all. To achieve an optimal healing outcome, the standard of care for most fractures consists of reduction followed by immobilization, with a myriad of options regarding the approach to fracture-healing. Currently, biopharmaceutical companies are sponsoring research with regard to products that aim to enhance or accelerate fracture-healing; however, as there are no approved and marketed systemic therapies for fracture-healing, the development and commercialization process for such products will require close collaboration between industry, academia, and regulators to determine how to bring these products to market in the most efficient manner. The following manuscript provides a brief overview of the regulatory process in the United States for systemic therapies in fracture-healing and discusses key issues that may arise in connection with the regulatory approval of these novel investigational treatments.