Evidence of a link between genetic variation of the serotonin transporter and depression and anxiety prompted the generation of serotonin transporter knockout mice. Loss of serotonin reuptake function in knock-outs causes reduced clearance of extracellular serotonin and associated alterations in serotonin neuronal firing and receptor function. Behavioral phenotyping function in knock-outs revealed genetic background-related abnormalities, including increased anxiety-like behaviors, reduced aggression, and exaggerated stress responses. Ongoing studies focus on identifying environmental, genetic, and developmental factors interacting with the htt mutation to produce these abnormalities. Serotonin transporter null mutant mice provide a model system to study how genetic variation in serotonin transporter function affects risk for neuropsychiatric disease.