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Antidepressant-, cocaine- and 3,4-methylenedioxymethamphetamine-sensitive serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) are expressed on presynaptic membranes of 5-HT-secreting neurons to provide efficient uptake of the biogenic amine after release. SERTs also support 5-HT transport across platelet, placental, gastrointestinal and pulmonary membranes and thus play a critical role in central nervous system and peripheral nervous system 5-HT signaling. SERTs are subject to multiple levels of posttranslational regulation that can rapidly alter 5-HT uptake and clearance rates. Specific cell surface receptors are now known to regulate SERT trafficking and/or catalytic function, with pathways activating protein kinase C, protein kinase G and p38 mitogen-activated protein kinase receiving the greatest attention. Remarkably, disease-associated mutations in SERT not only impact basal SERT activity but also selectively impact one or more SERT regulatory pathway(s). In this review, we describe both trafficking-dependent and trafficking-independent modes of SERT regulation and also the suspected roles played in regulation by SERT-associated proteins. Elucidation of the SERT 'regulome' provides important depth to our understanding of the likely origins of 5-HT-associated disorders and may help orient research to develop novel therapeutics.