Depressive disorders are among the most common psychiatric diseases, with prevalence estimates ranging from 5% to a maximum of 20%. Despite their high prevalence and socioeconomic impact, little is known about their etiology. Heritability estimates demonstrate up to a 50% genetic component based on family aggregation and contrasting monozygotic and dizygotic twin studies. The low relative risk to siblings ( lambda sib <1.5) makes the search for their genetic determinants very tedious. Gene-environment interaction has been recognized for a long time in the pathophysiology of depression, and its best biological substratum at present is represented by the serotonin transporter (5-HTT) gene, where several copies of its short allele culminate in depression and suicide in response to lifelong stress events. Many total genome scans have been performed with variable results, the most authoritative being the one of Utah pedigrees with a strong family history of major depression. It identified a locus on chromosome 12 encompassing a gene cluster and sex-specific predisposition. Nevertheless, recent genome scan meta-analysis yielded somewhat disappointing conclusions with a relatively low significance for quantitative trait loci on chromosomes 9, 10, 14, and 18. Studies on animal models have contributed to the chromosomal mapping of many behavioral traits, including anxiety, the stress response, and depression. Although F2 crosses constitute a classical approach, novel models of recombinant inbred strain and recombinant congenic strain animals allow for a rapid initial localization of any traits. This type of analysis has led us to uncover significant loci for the stress response and anxiety in rats and mice.