In this article, we raise the following question regarding the treatment of depression with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline: are there clinically relevant differences between these SSRIs in terms of their (i) pharmacodynamic and pharmacokinetic and (ii) clinical (i.e. efficacy, tolerability, adverse events and safety) profiles?In order to answer the first part of the question, the large body of literature on the pharmacodynamics and pharmacokinetics of SSRIs were examined. It can be concluded that, except for a few special situations (such as breast feeding), the many differences that the SSRIs show in their pharmacodynamic and pharmacokinetic profile are probably of limited importance in clinical practice.In order to answer the second part of the question, the 16 head-to-head comparisons between SSRIs that were published before January 1997 were reviewed. These were double-blind randomised studies that directly compared the SSRIs using a parallel group design; however, they were limited, quantitatively as well as qualitatively. The data published do not reveal unequivocal, clinically relevant differences between the SSRIs in terms of general efficacy, profile of action (e.g. effect on anxiety, agitation, sleep, suicidal ideation or cognitive function), speed of onset of action, total severity or profile of adverse events, or safety.We conclude that the differences between the SSRIs may lead the clinician when making a choice inindividualcases. However, at present, neither pharmacodynamic/pharmacokinetic considerations nor direct clinical comparisons between SSRIs provide data that can assist clinicians in making a rationalgeneralchoice between these drugs.