Pilot fatigue is a significant problem in modern aviation operations, largely because of the unpredictable work hours, long duty periods, circadian disruptions, and insufficient sleep that are commonplace in both civilian and military flight operations. The full impact of fatigue is often underappreciated, but many of its deleterious effects have long been known. Compared to people who are well-rested, people who are sleep deprived think and move more slowly, make more mistakes, and have memory difficulties. These negative effects may and do lead to aviation errors and accidents. In the 1930s, flight time limitations, suggested layover durations, and aircrew sleep recommendations were developed in an attempt to mitigate aircrew fatigue. Unfortunately, there have been few changes to aircrew scheduling provisions and flight time limitations since the time they were first introduced, despite evidence that updates are needed. Although the scientific understanding of fatigue, sleep, shift work, and circadian physiology has advanced significantly over the past several decades, current regulations and industry practices have in large part failed to adequately incorporate the new knowledge. Thus, the problem of pilot fatigue has steadily increased along with fatigue-related concerns over air safety. Accident statistics, reports from pilots themselves, and operational flight studies all show that fatigue is a growing concern within aviation operations. This position paper reviews the relevant scientific literature, summarizes applicable U.S. civilian and military flight regulations, evaluates various in-flight and pre-/postflight fatigue countermeasures, and describes emerging technologies for detecting and countering fatigue. Following the discussion of each major issue, position statements address ways to deal with fatigue in specific contexts with the goal of using current scientific knowledge to update policy and provide tools and techniques for improving air safety.