Genetic variation of the serotonin transporter (SCL6A4, 5-HTT) has been associated with fear- and anxiety-related behaviors, while a polymorphism in exon III of the D4 dopamine receptor gene (DRD4) has been linked to novelty seeking. The dopaminergic and the serotonergic neurotransmitter system have been found to modulate the amygdala-connected circuitries that are crucial in emotional modulation and response to fearful stimuli. Additionally, reactivity of amygdala-innervated effector systems is also essential for our understanding of anxiety-related behaviors. Here, we used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the impact of 5-HTTLPR and DRD4 on the cortisol stress response in 84 healthy adults. Saliva cortisol was measured during and after the Trier Social Stress Test. We found a significant main effect of DRD4: Carriers of the 7R allele exhibited lower cortisol responses. Additionally, a DRD4 by 5-HTTLPR interaction emerged: 5-HTTLPR LA/LA homozygotes showed a lower cortisol response than did S or LG allele carriers but only if they possessed at least one copy of the DRD4 7R allele. The results point to independent and joint effects of these polymorphisms on stress responsivity.