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This chapter summarizes trait-like (phenotypic) individual differences in neurobehavioral vulnerability to sleep deprivation, and current promising efforts to identify objective and biological markers of such differences. Sleep loss has increasingly become a major public health concern as population studies worldwide have found reduced sleep duration associated with increased risks of obesity, morbidity, and mortality. Available data suggest that common genetic variations (polymorphisms) involved in sleep-wake, circadian, and cognitive regulation may underlie symptomatic aspects of these large interindividual differences in neurobehavioral vulnerability to sleep deprivation in healthy adults. The impairing effects of sleep loss on neurobehavioral functions are the most well-established and conspicuous consequences of sleep deprivation. They include fatigue and sleepiness and unstable wakefulness; deficits in attention, working memory and executive functions; reduced mood-affect regulation; and increased accidents and injuries. Identifying who is likely to suffer neurobehavioral impairments would improve prevention of sleep deprivation and mitigation of its behavioral morbidity.