The clinical use of tricyclic antidepressants (TCAs) is often complicated by toxicity and safety problems due to their effects on multiple mechanisms of action, many of which are unnecessary for therapeutic effect. The development of the selective serotonin reuptake inhibitors (SSRIs), with their selective mode of action, has resulted in a class of antidepressant drugs possessing an improved side-effect profile, while retaining good clinical efficacy. Their introduction into clinical practice has led to enhanced patient compliance with antidepressant therapy and the ability to maintain treatment over longer periods of time at an adequate therapeutic dose. Although, as a result of their selective action, side-effects associated with SSRI therapy are minimised, distinct variations between individual SSRIs in terms of their tolerability profiles have been observed. The wealth of clinical data now available has revealed differences in their potential to cause psychiatric and neurological side-effects, dermatological reactions, anticholinergic side-effects, changes in body weight, sexual dysfunction, cognitive impairment, discontinuation reactions and drug-drug interactions. Patients who suffer from concomitant depression and physical illness may experience different tolerability profiles, in addition to the greater likelihood that they will be receiving concomitant medications with the potential for pharmacokinetic drug-drug interactions with coadministered SSRI therapy. In addition, the safety margin of SSRIs in overdose may vary within the group. Knowledge of the differences that exist among the SSRIs in respect of tolerability and safety will aid physicians in the selection of the most beneficial treatment strategy for their patients. A successful clinical outcome leads to a reduced economic burden for the patient, their family and the healthcare services. Thus, pharmacoeconomic considerations are also important in choosing antidepressant therapy. The SSRIs, despite relatively higher prescription costs, have been demonstrated to be a more cost-effective option than the TCAs. Furthermore, there is evidence that the emerging clinical differences between SSRIs may translate into significantly different economic outcomes within the group.