Today, 24-hour operations are necessary to meet the demands of our society and the requirements of our industrialized global economy. These around-the-clock demands pose unique physiological challenges for the humans who remain central to safe and productive operations. Optimal alertness and performance are critical factors that are increasingly challenged by unusual, extended, or changing work/rest schedules. Technological advancements and automated systems can exacerbate the challenges faced by the human factor in these environments. Shift work, transportation demands, and continuous operations engender sleep loss and circadian disruption. Both of these physiological factors can lead to increased sleepiness, decreased performance, and a reduced margin of safety. These factors can increase vulnerability to incidents and accidents in operational settings. The consequences can have both societal effects (e.g., major destructive accidents such as Three Mile Island, Exxon Valdez, Bhopal) and personal effects (e.g., an accident driving home after a night shift).