Young adolescents undergo rapid physical, cognitive, social, emotional, and sexual development, including puberty, sexual awareness, gender identity, physiological brain and cognitive growth, complex emotions, and impulse control. Tragically, thousands of adolescents die daily from mostly preventable causes such as violence, sexual health problems including HIV, communicable and noncommunicable diseases, poor nutrition, substance use, and suicide. Many more endure ill health due to these causes. In this article, we describe the risk factors related to bullying, homelessness, mental health, nutrition, sexual health, and substance use disrupting young adolescents' overall health and well-being. We report the prevalence of these risk factors in the United States and internationally, noting the myriad effects of each factor. We also identify intervention and prevention actions that countries, communities, school districts, schools, and individuals can take to reduce or forestall these risk factors for young adolescents. Lastly, we discuss comprehensive school health education/programs and articulate the principal issues that society needs to address to improve the health and well-being of young adolescents.