This study tested the 5‐HTTLPR gene as a moderator in the relation between maternal unresponsiveness and child externalizing symptoms in a disadvantaged, predominantly Black sample of two hundred and one 2‐year‐old children and their mothers. Using a multimethod, prospective design, structural equation model analyses indicated that maternal unresponsiveness significantly predicted increases in externalizing symptoms 2 years later only for children possessing the LL genotype. Moderation was expressed in a “for better” or “for worse” form hypothesized in differential susceptibility theory. In examining why the risk posed by maternal unresponsiveness differed across the 5‐HTTLPR polymorphism, mediated moderation analyses showed that children's angry reactivity to maternal negativity partly accounted for the greater susceptibility of homozygous L carriers to variations in maternal unresponsiveness.