Self-inflicted injury (SII) is a continuum of intentionally self-destructive behaviors, including nonsuicidal self-injuries, suicide attempts, and death by suicide. These behaviors are among the most pressing yet perplexing clinical problems, affecting males and females of every race, ethnicity, culture, socioeconomic status, and nearly every age. The complexity of these behaviors has spurred an immense literature documenting risk and vulnerability factors ranging from individual to societal levels of analysis. However, there have been relatively few attempts to articulate a life span developmental model that integrates ontogenenic processes across these diverse systems. The objective of this review is to outline such a model with a focus on how observed patterns of comorbidity and continuity can inform developmental theories, early prevention efforts, and intervention across traditional diagnostic boundaries. Specifically, when SII is viewed through the developmental psychopathology lens, it becomes apparent that early temperamental risk factors are associated with risk for SII and a range of highly comorbid conditions, such as borderline and antisocial personality disorders. Prevention efforts focused on early-emerging biological and temperamental contributors to psychopathology have great potential to reduce risk for many presumably distinct clinical problems. Such work requires identification of early biological vulnerabilities, behaviorally conditioned social mechanisms, as well as societal inequities that contribute to self-injury and underlie intergenerational transmission of risk.