Depression leads the higher personal and socio-economical burden within psychiatric disorders. Despite the fact that over 40 antidepressants (ADs) are available, suboptimal response still poses a major challenge and is thought to be partially a result of genetic variation. Pharmacogenetics studies the effects of genetic variants on treatment outcomes with the aim of providing tailored treatments, thereby maximizing efficacy and tolerability. After two decades of pharmacogenetic research, variants in genes coding for the cytochromes involved in ADs metabolism (CYP2D6 and CYP2C19) are now considered biomarkers with sufficient scientific support for clinical application, despite the lack of conclusive cost/effectiveness evidence. The effect of variants in genes modulating ADs mechanisms of action (pharmacodynamics) is still controversial, because of the much higher complexity of ADs pharmacodynamics compared to ADs metabolism. Considerable progress has been made since the era of candidate gene studies: the genomic revolution has made possible to assess genetic variance on an unprecedented scale, throughout the whole genome, and to analyze the cumulative effect of different variants. The results have revealed key information on the biological mechanisms mediating ADs effect and identified hypothetical new pharmacological targets. They also paved the way for future availability of polygenic pharmacogenetic panels to predict treatment outcome, which are expected to explain much higher variance in ADs response compared to CYP2D6 and CYP2C19 only. As the demand and availability of AD pharmacogenetic testing is projected to increase, it is important for clinicians to keep abreast of this evolving area to facilitate informed discussions with their patients.