Almost 15% of the full-time workers in the United States are shift workers. We review the physiologic challenges inherent not only in traditional night or rotating shifts but also in extended-duration shifts and other nonstandard hours. The challenging schedules of those in particularly safety-sensitive professions such as police officers, firefighters, and health care providers are highlighted. Recent findings describing the neurobehavioral, health, and safety outcomes associated with shift work also are reviewed. Comprehensive fatigue management programs that include education, screening for common sleep disorders, and appropriate interventions need to be developed to minimize these negative consequences associated with shift work.