During the last few years there is a growing concern about the increasing response to placebo seen in trials of antidepressants and the ever increasing difficulty in detecting the therapeutic signal. Even worse, recently there was much debate on the true usefulness of antidepressant therapy itself, especially after the publication of a meta-analysis by Kirsch et al in 2008. However the re-analysis of these data suggested that the correct drug-placebo difference is 2.18 or 2.68 instead of 1.80. Kirsch et al failed to report that that the change in HDRS score was 3.15 or 3.47 points for venlafaxine and 3.12 or 3.22 for paroxetine, which are above the NICE threshold. It is of prime importance that although a large percentage of the placebo response is due to expectancy this is not true for the active drug and effects are not additive. This might mean a distinct mechanism underlying the placebo and the drug effect. Also, the drug effect is always present and is unrelated to depression severity, while this is not true for placebo. It is interesting that by passing the years there seems to be an increasing absolute both placebo and drug effect but the effect size of the difference remains stable. Meta-analytic studies in larger data sets are necessary in order to further elucidate the relationship between the drug and the placebo response and the nature of the latter.