The current study examined the molecular genetic foundations of sensitive parenting in humans and is the first to test the interaction between genes and environment in modulating parental sensitive responses to children. In a community sample of 176 Caucasian, middle class mothers with their 23-month-old toddlers at risk for externalizing behavior problems, the association between daily hassles and sensitive parenting was investigated. We tested whether two dopamine-related genes, dopamine D4 receptor (DRD4) and catechol-O-methyltransferase (COMT) gene polymorphisms, modulate parents’ vulnerability to the negative influence of daily hassles on sensitive parenting behavior to their offspring. Sensitive parenting was observed in structured settings, and parents reported on their daily hassles through a standard questionnaire. In parents with the combination of genes leading to the least efficient dopaminergic system functioning (COMT val/val or val/met, DRD4-7Repeat), more daily hassles were associated with less sensitive parenting, and lower levels of daily hassles were associated with more sensitive parenting d = 1.12. The other combinations of COMT and DRD4 polymorphisms did not show significant associations between daily hassles and maternal sensitivity, suggesting differential susceptibility to hassles depending on parents’ dopaminergic system genes. It is concluded that the study of (multiple) gene–environment interactions (in the current case: gene by gene by environment interaction, G × G × E) may explain why some parents are more and others less impacted by daily stresses in responding sensitively to their offspring’s signals.