Substance use and addiction are disproportionately experienced by individuals with a history of exposure to early life stress (ELS), such as maltreatment, domestic violence and parent psychopathology. Unfortunately, extant interventions have mixed effectiveness at improving outcome trajectories for ELS-exposed children, who are often underserved by evidenced-based programs. Here, we employ a translational neuroscience framework to delineate how neuroscience can deepen our understanding of ELS-linked alterations in children's function to inform the development of more targeted, effective early intervention and addiction prevention programs. Candidate neural pathways altered by ELS and linked to addiction are described across sensory, affective, motivational, and executive function domains. Next, we provide an example of the application of translational neuroscience principles in a family of early interventions (i.e. Multidimensional Treatment Foster Care - Preschool, Kids in Transition to School) focused on improving self-regulation in ELS-exposed children. Future directions and areas of unmet need in intervention research detail the significant potential of translational neuroscience to advance interventionists' ability to support positive adjustment in ELS-exposed children and prevent harmful addiction outcomes.