Fatigue and workplace sleepiness are consequences of modern industrial society. Fatigue is a complex biological phenomenon that occurs as a function of time awake, time-of-day, workload, health, and off-duty lifestyle. Fatigue is a function of two major biological factors - the homeostatic drive for sleep and circadian rhythm of sleepiness. The greatest cause of fatigue is insufficient or disrupted sleep. Excessive sleepiness in the workplace and on highways is a serious safety hazard, and insufficient or disrupted sleep results in numerous accidents and adverse mental and physical health outcomes. Evidence-based strategies that promote better sleep and optimize work/rest schedules can mitigate the impact of fatigue and sleep loss. Proper nap and sleep scheduling, work breaks, modeling and monitoring tools, fatigue detection technologies, and pharmacological countermeasures can be implemented at home and/or in the workplace to reduce performance and safety hazards. Education about obtaining adequate sleep, the dangers of fatigue in terms of both health and cognitive consequences, and the availability of scientifically-proven sleep-enhancement and alertness-management strategies is essential.