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The function of serotonin transporters (SERTs) is related to mood regulation. Mice with deficient or reduced SERT function (SERT knockout mice) show several behavioral changes, including increased anxiety-like behavior, increased sensitivity to stress, and decreases in aggressive behavior. Some of these behavioral alterations are similar to phenotypes found in humans with short alleles of polymorphism in the 5-hydroxytryptamine (5-HT) transporter-linked promoter region (5-HTTLPR). Therefore, SERT knockout mice can be used as a tool to study 5-HTTLPR-related variations in personality and may be the etiology of affective disorders. This article focuses on the cellular and molecular alterations in SERT knockout mice, including changes in 5-HT concentrations and its metabolism, alterations in 5-HT receptors, impaired hypothala-mic-pituitary-adrenal gland axis, developmental changes in the neurons and brain, and influence on other neurotransmitter transporters and receptors. It also discusses the possible relationships between these alterations and the behavioral changes in these mice. The knowledge provides the foundation for understanding the cellular and molecular mechanisms that mediate the SERT-related mood regulation, which may have significant impact on understanding the etiology of affective disorders and developing better therapeutic approaches for affective disorders.