The etiology of early age onset substance use disorder (SUD), an Axis I psychiatric illness, isexamined from the perspective of the multifactorial model of complex disorders. Beginning atconception, genetic and environment interactions produce a sequence of biobehavioralphenotypes during development which bias the ontogenetic pathway toward SUD. One pathwayto SUD is theorized to emanate from a deviation in somatic and neurological maturation, which,in the context of adverse environments, predisposes to affective and behavioral dysregulation asthe cardinal SUD liability-contributing phenotype. Dysregulation progresses via epigenesis fromdifficult temperament in infancy to conduct problems in childhood to substance use by earlyadolescence and to severe SUD by young adulthood.