Injuries continue to be the leading cause of morbidity and mortality for children, adolescents, and young adults aged 1-24 years in industrialized countries in the twenty-first century. In this age group, injuries cause more fatalities than all other causes combined in the United States (U.S.). Importantly, many of these injuries are preventable. Annually in the U.S. there are >9 million emergency department visits for injuries and >16,000 deaths in children and adolescents aged 0-19 years. Among injury mechanisms, motor vehicle crashes, firearm suicide, and firearm homicide remain the leading mechanisms of injury-related death. More recently, poisoning has become a rapidly rising cause of both intentional and unintentional death in teenagers and young adults aged 15-24 years. For young children aged 1-5 years, water submersion injuries are the leading cause of death. Sports and home-related injuries are important mechanisms of nonfatal injuries. Preventing injuries, which potentially cause lifelong morbidity, as well as preventing injury deaths, must be a priority. A multi-pronged approach using legislation, advancing safety technology, improving the built environment, anticipatory guidance by clinical providers, and education of caregivers will be necessary to decrease and prevent injuries in the twenty-first century.