AbstractRecent work on the molecular genetics of complex traits in typical and atypical human development has focused primarilyon associations of single genes with behavior. Disparate literature suggests that the presence of one or two copies of the short allele of the serotonin transporter (5-HTT) gene and the long allele (7-repeat allele) version of the dopamine receptor D4 (DRD4) gene predicts internalizing- and externalizing-related behaviors, respectively. Apparently for the first time in the extant literature, we report a gene–gene statistical interaction on behavior problems in a group of typically developing children at age 7. DNA was extracted from buccal cells collected from 108 children and genotyped for short and long alleles of the5-HTTgene and the short (2–5 repeats) versus long (6–8 repeats) allele of theDRD4gene. Mothers completed the Child Behavior Checklist. As predicted, children with one or two copies of the short allele of the5-HTTgeneandthe long allele version of theDRD4gene exhibited significantly more internalizing and externalizing behaviors at age 7 than children with other combinations of the5-HTTandDRD4short and long genotypes. As well, children with the5-HTTlongand DRD4long genotypes had the lowest reported scores on internalizing and externalizing behaviors at age 7, suggesting that the presence of the5-HTTlong genotype may serve as a protective factor against these behaviors in children with the longDRD4genotype. Implications of these findings for understanding cumulative biological risk and protective factors in childhood behavior problems and psychopathology are discussed.