Among an impressive variety of identified serotonin receptors, 5-HT1A attracts particular attention due to its central role in the regulation of 5-HT-ergic neurotransmission and the data on its involvement in the mechanisms of stress response, aggressive behavior, anxiety, and depression. This review concentrates on the cross-regulation between 5-HT receptors and the implication of the 5-HT1A receptor in the genetic control of 5-HT-related behavior. Specifically, it describes the (1) functional interactions between 5-HT1A, 5-HT2A, 5-HT3, and 5-HT7 receptors; (2) cross-talk between 5-HT1A receptor and genes encoding key members of the brain 5-HT system; (3) implication of the 5-HT1A receptor in natural hibernation and genetic predisposition to different kinds of defensive behavior; and (4) role of 5-HT1A autoreceptors and heteroreceptors in anxiety, depression, and suicide, and in the antidepressant effect of serotonin reuptake inhibitors. This review provides converging lines of evidence that the 5-HT1A receptor contributes to the action of other 5-HT receptors, modulating their effect on behavior, and describes new data on the unique role of the 5-HT1A receptor in the indirect regulation of gene expression and in the autoregulation of the brain 5-HT system.