Major depressive disorder (MDD) is an emergent cause of personal and socio-economic burden, both for the high prevalence of the disorder and the unsatisfying response rate of the available antidepressant treatments. No reliable predictor of treatment efficacy and tolerance in the single patient is available, thus drug choice is based on a trial and error principle with poor clinical efficiency. Among modulators of treatment outcome, genetic polymorphisms are thought to explain a significant share of the inter-individual variability. The present review collected the main pharmacogenetic findings primarily about antidepressant response and secondly about antidepressant induced side effects, and discussed the main strengths and limits of both candidate and genome-wide association studies and the most promising methodological opportunities and challenges of the field. Despite clinical applications of antidepressant pharmacogenetics are not available yet, previous findings suggest that genotyping may be applied in the clinical practice. In order to reach this objective, further rigorous pharmacogenetic studies (adequate sample size, study of better defined clinical subtypes of MDD, adequate covering of the genetic variability), their combination with the results obtained through complementary methodologies (e.g., pathway analysis, epigenetics, transcriptomics, and proteomics), and finally cost-effectiveness trials are required. © 2013 Wiley Periodicals, Inc.