The selective serotonin reuptake inhibitors (SSRIs) antidepressants are at present time the most useful for the treatment of depression. SSRIs exhibit differences in potency of inhibiting serotonin reuptake, although the differences do not correlate with clinical efficacy. There are substantial pharmacokinetic differences among the five SSRIs, fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram. Optimum use of these drugs requires a working knowledge of these differences. Among these pharmacokinetic parameters, half-life and metabolism pathways are the most relevant. There are substantial differences in term of their half-life between fluoxetine and others SSRIs. The half-life of fluoxetine and its active metabolite norfluoxetine is respectively 2 to 4 days and 7 to 15 days, more extended than other SSRIs (approximately 1 day). The extended half-life of fluoxetine and its active metabolite may be an advantage in the poorly compliant patient and may offer a potential safety advantage over shorter-acting SSRIs, with respect to abrupt discontinuation of therapy. Conversely, this long half-life needs a long period of wash-out (5 weeks) before introducing other drugs (MAOIs, sumatriptan) which can interact with serotonin function and can lead to the serotoninergic syndrome. SSRIs are potent inhibitors of the hepatic isoenzyme P450-2D6 and would be expected to have effects on the clearance of drugs metabolized by this enzyme. Paroxetine is the most potent inhibitor, followed by fluoxetine, sertraline, citalopram and fluvoxamine. The metabolite elimination of citalopram, paroxetine and fluvoxamine is delayed by renal disease and dosages should be lowered in elderly patients. Conversely the pharmacokinetic of fluoxetine and sertraline are not affected by either age or renal impairment and, for fluoxetine, by obesity.