Interindividual differences in neurobehavioral response to sleep loss are ubiquitous and unexplained. Numerous factors have been examined as potential predictors of phenotypic response to sleep loss but none have yielded a comprehensive view of the phenomenon. This dissertation examines the impact of baseline factors, habitual sleep patterns, and homeostatic response to sleep loss on accrued deficits in psychomotor vigilance during chronic partial sleep restriction, using the largest study sample to date. A total of 306 healthy adults completed controlled isolated laboratory protocols for 11-20 days and were randomized to either chronic partial sleep restriction (five consecutive nights of four hours time in bed) or control condition (ten hours time in bed on all nights). Findings indicate no significant impact of personality, academic intelligence, subjective reports of chronotype, sleepiness and fatigue, performance on working memory, and demographic factors such as sex, ethnicity, and body mass index, on vulnerability to the negative effects of sleep loss on psychomotor vigilance. Superior baseline performance on the PVT, older age, and ability to sustain wakefulness on the MWT were associated with relative resilience to decrements in vigilant attention during sleep restriction. Interindividual differences in vulnerability to the effects of sleep loss were not accounted for by prior sleep history, habitual sleep patterns outside of the laboratory, baseline sleep architecture, or homeostatic sleep response during chronic partial sleep restriction. Variability in a modulatory drive responsible for integrating competing signals for wakefulness and sleep may partially account for phenotypic vulnerability to the effects of sleep loss.