Physician burnout threatens the well-being and sustainability of the health care workforce. This large prospective cohort study found that 45% of resident physicians experienced burnout. Higher burnout rates were detected in urology, general surgery, emergency medicine, and neurology residents (relative to internal medicine residents). The overall prevalence of burnout was similar to studies of practicing physicians, and significantly higher than studies of the general population. Although most residents were satisfied with their career choice, those who were burned out were more likely to regret their decision to become a physician. An Annual Perspective explored how burnout impacts patient safety.