Physician burnout and other forms of occupational distress are a significant problem in modern medicine, especially during the COVID19 pandemic, yet few doctors are familiar with the neurobiology that contributes to these problems. Burnout has been linked to changes that reduce a physician’s sense of control over their own practice, undermine connections with patients and colleagues, interfere with work–life integration, and result in uncontrolled stress. Brain research has demonstrated that uncontrollable stress, but not controllable stress, impairs the functioning of the prefrontal cortex, a recently evolved brain region that provides top-down regulation over thought, action and emotion. The prefrontal cortex governs many cognitive operations essential to physicians, including abstract reasoning, higher order decision-making, insight, and the ability to persevere through challenges. However, the prefrontal cortex is remarkably reliant on arousal state, and is impaired under conditions of fatigue and/or uncontrollable stress when there are inadequate or excessive levels of the arousal modulators (e.g. norepinephrine, dopamine, acetylcholine). With chronic stress exposure, prefrontal gray matter connections are lost, but can be restored by stress relief. Reduced PFC self-regulation may explain several challenges associated with burnout in physicians including reduced motivation, unprofessional behavior, and suboptimal communication with patients. Understanding this neurobiology may help physicians have a more informed perspective to help relieve or prevent symptoms of burnout, and may help administrative leaders to optimize the work environment to create more effective organizations. Efforts to restore a sense of control to physicians may be particularly helpful.