The arrival of the Journal's 175th anniversary occurs at a time of recent advances in research, providing an ideal opportunity to present a neuro developmental roadmap for understanding, preventing, and treating psychiatric disorders. Such a roadmap is particularly relevant for early-childhood-onset neuro developmental conditions, which emerge when experience dependent neuroplasticity is at its peak. Employing a novel developmental specification approach, this review places recent neuro developmental research on early childhood disruptive behavior within the historical context of the Journal. The authors highlight irritability and callous behavior as two core exemplars of early disruptive behavior. Both phenotypes can be reliably differentiated from normative variation as early as the first years of life. Both link to discrete pathophysiology: irritability with disruptions in prefrontal regulation of emotion, and callous behavior with abnormal fear processing. Each phenotype also possesses clinical and predictive utility. Based on a nomologic net of evidence, the authors conclude that early disruptive behavior is neuro developmental in nature and should be reclassified as an early-childhood-onset neuro developmental condition in DSM-5. Rapid translation from neuro developmental discovery to clinical application has transformative potential for psychiatric approaches of the millennium.