Depression is a prevalent and increasing concern in primary care, particularly among adolescents. Evidence supports routine screening, which improves remission and symptom reduction in adults and perinatal populations. Both psychotherapy and pharmacotherapy are effective first-line treatments, with similar efficacy in reducing symptoms. Selective serotonin reuptake inhibitors (SSRIs) remain the preferred outpatient antidepressant, demonstrating superiority over placebo and comparable outcomes to other agents. Generally safe for pregnant, breastfeeding, and geriatric patients, SSRIs require thoughtful selection based on side effects, contraindications, and patient preferences. Primary care clinicians are central to providing individualized, evidence-based, and patient-centered management of depression.