This chapter reviews the evidence for first-line treatment of major depressive disorder (MDD), and strategies for patients with treatment-resistant depression. Many trials have investigated the efficacy of selective serotonin reuptake inhibitors (SSRIs) compared with other antidepressants. Patients with MDD are at higher risk of suicide, and guidelines indicate that patients should be assessed for suicide at the start of treatment and regularly over the course of treatment. As augmenting agents, atypical antipsychotics, lithium, and triiodothyronine (T3) have been studied the most extensively, and shown to have benefit. However, their risks and side-effect profiles may make them less attractive to patients, and patient preference and safety should determine treatment decisions for refractory or chronic MDD. The use of biomarkers, including pharmacogenetic testing, may one day provide more accurate predictors of response or adverse outcomes, allowing targeted treatments and the promise of personalized medicine.