The goal of this Series paper is to show how road safety has evolved as a global public health issue over the past two decades and to discuss the political and economic dynamics that led to this change. Specifically, the key stakeholders, influences, networks, issue framing, actor power, and synergistic interactions that have contributed to how road safety has evolved as a global public health issue will be discussed. In doing so, we capture the important chronology of events and discuss a set of challenges that highlight the complexity of road safety. We posit that the global road safety community needs to re-evaluate its role and strategy for the next decade and focus more on implementation and country action to achieve reductions in road traffic injuries. We call for an open and inclusive process to ensure that such a reflection occurs before the end of the current decade.