There are considerable individual differences in cognitive performance deficits resulting from extended work hours and shift work schedules. Recent progress in sleep and performance research has yielded new insights into the causes and consequences of these individual differences. Neurobiological processes of sleep/wake regulation underlie trait individual variability in vulnerability to performance impairment due to sleep loss. Trait vulnerability to sleep loss is observed in the laboratory and in the work environment, even in occupational settings where (self-)selection pressures are high. In general, individuals do not seem to accurately assess the magnitude of their own vulnerability. Methods for identifying workers who are most at risk of sleep loss-related errors and accidents would therefore be helpful to target fatigue countermeasure interventions at those needing them most. As yet, no reliable predictors of vulnerability to sleep loss have been identified, although candidate genetic predictors have been proposed. However, a Bayesian forecasting technique based on closed-loop feedback of measured performance has been developed for individualized prediction of future performance impairment during ongoing operations. Judiciously selecting or monitoring individuals in specific tasks or occupations, within legally and ethically acceptable boundaries, has the potential to improve operational performance and productivity, reduce errors and accidents, and save lives. Trait individual variability in responses to sleep loss represents a major complication in the application of one-size-fits-all hours of service regulations--favoring instead modern fatigue risk management strategies, because these allow flexibility to account for individual vulnerability or resilience to the performance consequences of extended work hours and shift work schedules.