--- - |2 Abstract Low executive function (EF) during early childhood is a major risk factor for developmental delay, academic failure, and social withdrawal. Susceptible genes may affect the molecular and biological mechanisms underpinning EF. More specifically, genes associated with the regulation of prefrontal dopamine may modulate the response of prefrontal neurons during executive control. Several studies with adults and older children have shown that variants of the catechol‐O‐methyltransferase (COMT) gene are associated with behavioral performance and prefrontal activations in EF tasks. However, the effect of the COMT genotype on prefrontal activations during EF tasks on young children is still unknown. The present study examined whether a common functional polymorphism (Val158Met) in the COMT gene was associated with prefrontal activations and cognitive shifting in 3‐ to 6‐year‐old children. The study revealed that, compared with children with at least one Met allele (Met/Met and Met/Val), children who were Val homozygous (i) were more able to flexibly switch rules in cognitive shifting tasks and (ii) exhibited increased activations in lateral prefrontal regions during these tasks. This is the first evidence that demonstrates the relationship between a gene polymorphism and prefrontal activations in young children. It also indicates that COMT Val homozygosity may be advantageous for cognitive shifting and prefrontal functions, at least during early childhood, and children who possess this variant may have a lower risk of developing future cognitive and social development issues. - Developmental Science, Volume 21, Issue 5, September 2018.