Depression is common in primary care settings, affecting at least 10% of primary care patients. It carries medical and psychiatric comorbidity, increasing the risk of cardiovascular disease, diabetes, hypertension, stroke, medically unexplained (functional) symptoms, chronic pain, anxiety disorders, and substance abuse. Diagnosis and treatment are straightforward for many patients. The greatest current challenge is to recognize and relieve symptoms of treatment-resistant depression. This article reviews current approaches to diagnosing and treating depression, especially treatment-resistant forms of depression.