In the United States (U.S.), premature mortality in adulthood from suicide, alcohol-related disease, and substance overdoses has increased steadily over the past two decades. To better understand these trends, it is necessary to first examine the harmful behaviors that often precede these preventable deaths (i.e., suicidal ideation and attempts, and harmful alcohol and substance use). Representing critical developmental periods in which psychopathology is most likely to emerge, childhood and adolescence provide an informative lens through which to investigate susceptibility to harmful behaviors. This article synthesizes current evidence describing these rising U.S. mortality rates and the prevalence rates of harmful behaviors linked to these types of mortality. A brief selective review of longitudinal research on harmful behaviors in relation to the most relevant categories of child and adolescent psychopathology is then provided. Finally, recommendations for future research and implications for prevention are discussed.