The serotonin (5-hydroxytryptamine [5-HT]) and noradrenalin (NA) reuptake inhibitor duloxetine is currently the only widely approved pharmacological treatment option for women with stress urinary incontinence (SUI). The rationale for employing duloxetine in SUI is based on the role of 5-HT and NA in the neurological control of the lower urinary tract. Animal studies have shown that duloxetine increases the concentration of 5-HT and NA in the sacral spinal cord, thereby facilitating an increased activity of the external urethral sphincter (rhabdosphincter) and preventing urine leakage during the storage phase of the micturition cycle. Importantly, 5-HT and NA exert only a modulatory effect as they are not able to directly excite motor neurons. Glutamate is the key descending neurotransmitter and can be considered as the ‘on/off’ switch for micturition. In the absence of glutamate, no rhabdosphincter activity is observed, irrespective of the presence of 5-HT and NA. Hence, duloxetine enhances sphincter activity during urine storage when glutamate is released but allows complete relaxation of the rhabdosphincter once glutamate release is inhibited during the voiding phase. The efficacy of duloxetine for treating women with SUI, as shown in several double-blind, placebo-controlled randomised clinical trials, has suggested a similar mode of action, although no direct evidence for this pathway in humans was available until recently. Two recent studies provide support for duloxetine's mechanism of action in humans. Duloxetine was shown to have a significant effect on the excitability of pudendal motor neurons and on sphincter contractility in healthy women. In contrast, no relevant effect was observed on urethral resting tone. Another study reported important increases in Valsalva leak point pressure and in the rhabdosphincter electrical activity at rest and with coughing in women with SUI who responded to duloxetine. These studies support the hypothesis that duloxetine in women with SUI enhances urethral closure through neuromodulation of the rhabdosphincter.