Yearly, more than 1.2 million people are killed by road traffic injuries (RTIs) around the globe, and another 20 to 50 million are injured. The global burden of RTIs is predicted to rise. We explored the need for concerted action for global road safety and propose characteristics of an effective response to the gap in addressing RTIs. We propose that a successful response includes domains such as strong political will, capacity building, use of evidence-based interventions, rigorous evaluation, increased global funding, multisectoral action, and sustainability. We also present a case study of the global Road Safety in 10 Countries project, which is a new, 5-year, multipartner initiative to address the burden of RTIs in 10 low- and middle-income countries.