Major depressive disorder (MDD) is the most predominant mental disorder in the United States, with serious and costly health risks if not successfully managed. Pharmacotherapy is a standard option for MDD treatment, but patients often require extensive therapy adjustments to find a suitable regimen. Pharmacogenomics may enable greater precision in antidepressant therapy. Genotypic variations in CYP2D6 and CYP2C19 metabolic enzymes are reliable predictors of serum drug concentration, but the complex dose-response relationship of antidepressants prevents such variations from predicting therapy success. Additionally, ABCBl has been examined for its role in P-glycoprotein efflux of antidepressants in the brain, yet it is still inconclusive as to which variations are correlated with drug response. Current genotypic guidelines are largely proactive and clinical trials utilizing genotypic dosing have shown significant reductions in side effects and health care costs. Further studies of genotypic targets are needed and, if the possible clinical benefits are confirmed, the use of genotyping will be an important tool in optimizing antidepressant therapy.