Shift work has been associated with a number of health problems including cardiovascular disease, impaired glucose and lipid metabolism, gastrointestinal discomfort, reproductive difficulties, and breast cancer. The specific contributions of disturbed physiological rhythms, circadian misalignment, and sleep debt to the various medical problems encountered by shift workers remain to be clarified. Fatigue can be caused by extended on-duty and/or waking periods, inadequate sleep quantity, sleep disturbances, disruption of circadian rhythms, and difficult work and familial conditions. Fatigue-related accidents raise a safety concern for shift workers, especially at the end of the night when the circadian nadir of alertness interacts with increased time awake. Individuals vary greatly in their capacity to adjust to atypical work schedules and their tolerance to circadian misalignment. Predisposing individual and domestic factors have been identified, such as increasing age, being a single woman in charge of children, and split sleep patterns, all of which can affect the ability to adjust to atypical schedules. However, prior studies indicate that predisposing individual and social determinants are generally poor predictors of shift work tolerance in a given individual. In this manuscript, we review several countermeasures to improve adaptation to shift work.