Established antidepressants including tricyclic antidepressants (TCAs), tetracyclic antidepressants and monoamine oxidase inhibitors (MAOIs) affect a series of neurotransmitter functions. In the debate of clinical efficacy much attention has focused on the uptake of noradrenaline (NA) and serotonin (5-HT) as a means to increase neuronal activity. Most antidepressants, whether classic or new, inhibit the uptake of either one or the other or both transmitters. Besides that, all of the classical antidepressants potently inhibit a series of neurotransmitter receptors. A series of newer antidepressants preferentially increase 5-HT transmission by inhibiting 5-HT uptake. Selective serotonin reuptake inhibitors (SSRIs) are those which preferably inhibit 5-HT uptake compared with NA, and which at the same time have no or only slight effect on other uptake mechanisms, neurotransmitter receptors, enzymes, etc. Five SSRIs are currently marketed, i.e. citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. They all fulfil the above-mentioned criteria. Citalopram is the most selective 5-HT-uptake inhibitor, whereas paroxetine is the most potent. By and large the rank order of selectivity is equal in in vitro studies, in biochemical in vivo studies and in behavioural studies. Selectivity and potency for 5-HT uptake do not coincide. The selectivity of SSRIs is also founded on the lack of inhibition of receptors for different neurotransmitters, e.g. acetylcholine, histamine, NA, 5-HT or dopamine (DA), as well as monoamine oxidase (MAO). Citalopram, fluoxetine and sertraline are metabolized to compounds possessing similar properties as the parent drugs, whereas this is not the case with the metabolites of fluvoxamine and paroxetine. Upon repeated administration SSRIs maintain the selective and potent inhibition of 5-HT uptake. Although repeated treatment with TCAs and electroconvulsive shocks leads to changes in receptor number and pharmacological responsiveness, e.g. down-regulation of β-adrenoceptors and down-regulation of 5-HT2A -mediated function, no consistent changes are seen after prolonged treatment with SSRIs. Since the marketed SSRIs all show clear antidepressant effect, this receptor regulation seems not to be a prerequisite for clinical antidepressant activity.