Physicians today experience unprecedented stress and distress, as evidenced by reports of escalating rates of burnout, dissatisfaction with life-work balance and career choice, occurrence of major depressive disorder (MDD) and substance use and misuse, and unacceptable rates of physician suicide. While efforts to ameliorate physician burnout are heartening, a major concern remains: physician depression and suicide prevention are relatively ignored, in part fueled by the fact that burnout and MDD have overlapping symptoms and clinical features. This imbalance may also reflect the ongoing stigma, even among physicians, of mental illness and its treatment. In contrast, the term burnout, which indicates a human reaction to something outside oneself, is less stigmatized, allowing it to become a catchall term for emotional distress. However, erroneously labeling a physician’s distress as burnout may prevent or delay appropriate treatment of MDD, a serious and sometimes life-threatening mental disorder. This brief perspective discusses the complex association of burnout with depression and provides guidelines for diagnosing depression in the context of work stress.