The highly specific mechanism of action of the selective serotonin re-uptake inhibitors (SSRIs) confers advantages on this group, relative to other classes of antidepressant, and thus represents a significant advance in the pharmacotherapy of depression. Whilst their clinical efficacy is equivalent to that of the tricyclic antidepressants (TCAs), the SSRIs have a greatly reduced risk of toxicity in overdose and have been shown to be significantly better tolerated. Specifically, the SSRIs have a low incidence of anticholinergic effects and are essentially devoid of cardiotoxicity. This tolerability advantage may be of significance in improving compliance and hence cost-effectiveness of treatment, particularly in the long term. Despite a lack of sedative effect, there is evidence that SSRIs are more effective than TCAs in the treatment of depression with anxiety. In addition, the SSRIs have been shown to be effective in obsessive-compulsive disorder, panic disorder and social phobia. Although superior efficacy has not been demonstrated for any one of the SSRIs, the structural diversity of this group is reflected in emerging qualitative and quantitative differences in side effects and drug interaction potential. Many of these differential features reflect important variations in pharmacological and pharmacokinetic profiles, including dosage flexibility, washout times, dose-plasma level proportionality and age-related changes in plasma levels. Fluoxetine, for example, has a considerably longer half-life than other SSRIs and side effects and drug interactions may thus occur for an extended period following discontinuation of treatment. Significant differences in the potential for drug interactions in this group are related to their relative potency for inhibition of important liver drug-metabolising enzymes including CYPIID6, CYPIA2 and CYPIIIA4. Large comparative clinical trials of the different SSRIs have yet to be undertaken; however, the differences that have already become apparent provide important information enabling the physician to choose an SSRI appropriate to the individual patient.