It is important to evaluate a new antidepressant in terms of its efficacy in relation to that of reference agents such as the tricyclics and monoamine oxidase inhibitors. Newer antidepressants have not been shown to be more effective than the reference agents, either in the proportion of patients in whom they produce a therapeutic response or in their speed of onset of antidepressant activity. The serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine appears to offer some advantages in both of these areas. In a number of short-term placebo- and comparator-controlled trials, venlafaxine was shown to be as effective as, and in some cases more effective than, the reference antidepressants. These findings were also substantiated in meta-analyses of both short-term and long-term comparator-controlled studies. In terms of its onset of activity, venlafaxine was shown to produce statistically significant differences from placebo as early as Day 4 in a study in severely depressed in-patients with melancholia and by Week 1 in a study in out-patients with major depression. A rationale is presented to define the clinical relevance of these findings.