Although heritability of affective disorders is well accepted, several questions are still unsolved. The phenotype associated with the disorder is still uncertain, e.g., different disorders of the affective spectrum could be observed in the family of the patient. Furthermore, genetic studies failed to provide exact explanation for these questions either. We reported first that the role of the promoter region variant (5-HTTLPR) is not exclusive, and the middle region (tagged by the SNP rs140700) of the gene has also a significant role in the G x E model. Furthermore, we discovered a significant Gene x Gene x Environment interaction between 5-HTTLPR, rs140700 and threatening life events. Haplotype analyses of the serotonin transporter gene suggested that the majority of the S allele carriers for 5-HTTLPR with multiple threatening life events expressed high depression score, however, a subgroup with much lower depression score was also identified. In another study, interaction of 5-HTTLPR with the cannabinoid receptor 1 gene promoter was significantly associated with anxious phenotype. These results suggest that extremely high or low synaptic serotonin concentration could be associated with a high anxiety score. These findings call attention to the serotonergic dysfunction in the vulnerability for affective disorders.