Background: The capacity to control or regulate one's emotions, cognitions and behavior is central to competent functioning, with limitations in these abilities associated with developmental problems. Parenting appears to influence such self-regulation. Here the differential-susceptibility hypothesis is tested that the more putative "plasticity alleles" adolescents carry, the more positively "and" negatively influenced they will be by, respectively, supportive "and" unsupportive parenting. Methods: One thousand, five hundred and eighty-six (1586) adolescents (n = 754 males; n = 832 females) enrolled in the American Add Health project were scored in terms of how many of 5 putative "plasticity alleles" they carried--the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, the short allele of 5HTTLPR, and the 2R/3R alleles of MAOA. Then the effect of the resultant index (ranging from 0 to 5) of cumulative-genetic plasticity in moderating effects of parenting on adolescent self-regulation was evaluated. Results: Consistent with differential susceptibility, the more plasticity alleles males (but not females) carried, the more "and" less self-regulation they manifested under, respectively, supportive and unsupportive parenting conditions. Conclusion: Adolescent males appear to vary for genetic reasons in their susceptibility to parenting vis-a-vis self-regulation, perhaps due to epistatic and/or epigenetic processes. GxE research may benefit from compositing candidate genes. To afford comparative evaluation of differential-susceptibility vs. diathesis-stress models of environmental action, future GxE work should focus on positive as well as negative environmental conditions and developmental outcomes.