The present study demonstrates the interplay between interparental relationship satisfaction and child plasticity in the origins of internalizing problems in 99 community mothers, fathers, and children. Our cumulative measure of plasticity integrated genetics (5-HTTLPR polymorphism), psychophysiology (skin conductance level), and observed behavior (inhibition, sadness, joy). The interaction between plasticity and interparental relationship satisfaction reflected differential susceptibility. Compared with low-plasticity peers, high-plasticity children had more internalizing problems from 5.5 to 12 years when the interparental relationship at 4.5 years was acrimonious, but fewer problems when it was harmonious. Further, almost half of the children in this sample were “differentially affected” by the interaction such that greater plasticity was associated with fewer internalizing problems when their parents had a harmonious relationship, a key feature of differential susceptibility.