The etiology of behavioral precursors to substance misuse and aggression is viewed from the perspective of a developmental, multifactorial model of complex disorders. Beginning at conception, genetic and environmental interactions have potential to produce a sequence of behavioral phenotypes during development that bias the trajectory toward high-risk outcomes. One pathway is theorized to emanate from a deviation in neurological development that predisposes children to affective and cognitive delays or impairments that, in turn, generate dysregulatory behaviors. The plasticity of these neurobiological systems is highly relevant to the prevention sciences; their functions are reliant upon environmental inputs and can be altered, for better or for worse, contingent upon the nature of the inputs. Thus, social contextual factors confer significant influence on the development of this neural network and behavioral outcomes by increasing risk for, or protecting (1) against, dysregulatory outcomes. A well-designed intervention can exploit the brain's plasticity by targeting biological and social factors at sensitive time points to positively influence emergent neurobiological functions and related behaviors. Accordingly, prevention research is beginning to focus on perturbations in developmental neural plasticity during childhood that increase the likelihood of risky behaviors and may also moderate intervention effects on behavior. Given that the more complex features of neurobiological functions underlying drug misuse and aggression (e.g., executive cognitive function, coping skills, affect regulation) do not coalesce until early adulthood when prefrontal-limbic brain networks consolidate, it is critical that mechanisms underlying developmental risk factors are identified. An empirically driven prevention approach, thus, may benefit from consideration of (i) the type, effect, and developmental timing of the environmental impact on the brain, and (ii) the type and effect on brain function, and developmental timing of the intervention. This translational approach promises to eventually offer some direction for the design of effective interventions to prevent drug misuse and concomitant aggression.