Children with severe antisocial behavior have an increased risk of showing violently aggressive and other forms of problem behavior in adolescence and adulthood. It is well established that both biological and social factors are involved in the development of antisocial behavior. The primary aim of this paper is to discuss the evidence that specific neurobiological systems are involved in the etiology of childhood-onset antisocial behavior. These factors are responsible for the severity of the behavioral problems observed in antisocial children, but they also play a role in their persistence, because they influence children's interactions with their environment. We will discuss the possible causes of disruptions in neurobiological systems in childhood antisocial behavior and point out the implications of these findings for theory and clinical practice. We will argue that familial factors (e.g., genetic influences, early childhood adversity) are linked to negative behavioral outcomes (e.g., antisocial behavior problems) through the mediating and transactional interplay with neurobiological deficits. An investigation of neurobiological functioning in antisocial children might not only indicate which children are most likely to persist in engaging in severe antisocial behavior, but also guide the development of new interventions.