Alcohol dependence is characterized by frequent, compulsive and uncontrolled consumption of alcohol associated with behavior of maladaption and destruction. It is an etiologically and clinically heterogeneous syndrome, moderately to highly heritable, and caused by interaction of genes and environment. Alcohol dependence is related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioral control as well as anxiety and stress response. Alcohol induces adaptive changes in brain function providing the basis for tolerance, craving, withdrawal, and emotional disturbance. The differentiation of psychobiological traits of addictive behavior reflecting neurobiological processes is therefore of particular importance for the dissection of the complex genetic susceptibility to alcohol dependence. A central serotonin (5-HT) deficit is thought to be involved in the pathogenesis of alcohol dependence by modulating motivational behavior, neuroadaptive processes, and resulting emotional disturbance. 5-HT-related impulsive, aggressive, and suicidal behavior has been linked to a primordial personality that is susceptible to alcohol dependence. Although variations in many of the genes that encode receptors, enzymes, and transporters of the 5-HT system have been tested as risk factors for alcohol dependence, genetic analyses of 5-HT signaling in alcohol dependence have mainly been focused on the 5-HT transporter (5-HTT) gene. Due to its central role in the fine-tuning serotonergic neurotransmission, a regulatory variant of the 5-HTT, which is associated with anxiety related traits, is not only a key player in the neurobiological mechanism of gene x environment interaction in the etiology of depression, but also contributes to the risk to develop alcohol dependence with antisocial behavior and suicidality. Evidence for a modulatory effect of allelic variation of 5-HTT function on limbic circuit responses to emotional stimuli suggests that genotype-endophenotype correlations may be accessible to molecular functional imaging of the brain. These new developments have broad implications for our understanding how genetic vulnerability to alcohol dependence is manifested in the brain's response to emotional stimuli.