In alcoholism, central serotonergic dysfunction may contribute to negative affect and impulsive aggression. In animal experiments and human studies, serotonin transporters and receptors interact with central processing of affectively negative stimuli. Monoamine effects on central processing of emotionally salient stimuli are genetically influenced, and besides single gene effect, gene-gene interactions have been postulated. Gene-gene effects are often assumed but difficult to test in behavioral genetics due to the small explained behavioral variance. Processing of unpleasant stimuli in the amygdala has been associated with a functional polymorphism (val158-met)in the catechol-O-methyltransferase (COMT) gene and independently with a functional polymorphism in the regulatory region of the serotonin transporter (5-HTT) gene. 5-HTT function may also be affected by a recently detected A/G exchange in the long allele (insertion)of the 5-HTT regulatory region. In individuals with more COMT met158 alleles and with more s or lG alleles of the 5-HTT regulatory region, aversive stimuli elicited greater neuronal activity in the bilateral amygdalae and hippocampi. These genotype effects were additional to amygdala and hippocampus activation by aversive versus neutral stimuli, indicating that COMT val158-met and 5-HTT genotype were additionally associated with increased processing of aversive stimuli in the amygdalae. Functional brain imaging may be used to assess the interaction of multiple genotypes with anxiety and impulsive aggressiveness in alcohol-dependent patients.