This chapter focuses on the fatigue that stems primarily from the schedules that support the aviation mission. It demonstrates the fatigue is associated with slower brain activity, changes in eye movements and pupillary responses, and other physiological differences that persist despite the presence of worker incentives or considerable individual effort. Fatigue is a major human-factors hazard because it affects most aspects of a crewmember's ability to safely perform his or her job. In aviation, fatigue has long been recognized as a problem by aircrews, but the impact of inadequate pilot alertness on safety historically has been underappreciated. The chapter concerns about the adverse impact of aircrew fatigue have long been recognized in military aviators because of the nature of military and wartime operations. According to the American College of Occupational and Environmental Medicine, fatigue issues are responsible for more than $136 billion per year in health-related lost productivity each year.