Serotonin transporter (SERT) mediates the intracellular reuptake of released serotonin, thus regulating its biological functions. Abnormalities in serotonin reuptake can alter enteric serotonergic signalling, leading to sensory, motor and secretory gut dysfunctions, which contribute to the pathophysiology of irritable bowel syndrome (IBS). This relationship has fostered the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of IBS. Current data on the efficacy of SSRIs in IBS, association of the SERT gene promoter polymorphism 5-HTTLPR with IBS and the expression pattern of SERT in the intestinal mucosa of IBS patients are conflicting. Recent molecular studies have raised critical questions about multiple SERT mRNA transcripts in the human gut, the role of polymorphic SERT promoter in the regulation of enteric SERT expression and the ability of 5-HTTLPR to affect human SERT gene transcription. The present review highlights recent advances in SERT genetics, discusses their implications for potential therapeutic applications of SSRIs in IBS and presents original suggestions for future investigations.