Burnout is the experience of three interrelated components: exhaustion, cynicism and inefficacy. To mitigate the effects of burnout and help prevent it in the future, health system leaders must address the root causes of what many have deemed a health crisis of epidemic proportions. In this article, ten prominent health system CEOs examine the widespread issue of physician burnout, its main contributors, leaders’ role in responding to burnout, and an 11-item call to action.