Both maternal depressive symptoms and infants' dopamine-related genetic characteristics have been linked to infants' hypothalamic-pituitary-adrenal (HPA) functioning. This study investigated the interactive influence of maternal depressive symptoms and infant DRD2 and SLC6A3 genotypes on infant cortisol reactivity; whether this interaction reflects diathesis-stress or differential susceptibility; and whether this interaction influences the flexibility of the infant cortisol response across challenges known to exert differential effects on infant cortisol reactivity. A community sample of 314 mother-infant dyads participated in toy frustration (age 16 months) and maternal separation (age 17 months) challenges, and salivary cortisol was collected at baseline, +20, and +40min. Maternal depressive symptoms were assessed with the Beck Depression Inventory-II at infant age 16 months. Infant buccal cells were collected at both time points for genotyping. DRD2 and SLC6A3 genotypes moderated the relation between maternal depressive symptomatology and infant cortisol reactivity in a diathesis-stress manner in the context of toy frustration, and in a differential susceptibility manner in the context of maternal separation. Higher levels of maternal depressive symptoms predicted reduced cortisol flexibility across challenges for infants with at least one A1 allele of DRD2 and infants with the 10/10 genotype of SLC6A3. Results suggest that maternal depressive symptomatology is related to infants' cortisol reactivity and to the flexibility of that reactivity across psychosocial challenges, but this relation is dependent on the infant's genetic characteristics.