This chapter focuses on two recent studies capitalizing on inter-individual differences in response to increased sleep homeostasis and misalignment between the circadian signal and sleep to better characterize the brain mechanisms involved in the maintenance of wakefulness and associated cognitive processes. Extreme chronotypes are characterized by marked differences in their preferred timing for sleep and wakefulness, as well as optimal times of day to perform cognitively demanding tasks. A study detailed in the chapter used a genetic trait as a means to characterize the regulation of cognitive performance throughout a normal waking day and following total sleep deprivation. A variable-number-of-tandem-repeat (VNTR) polymorphism in the coding region of the clock gene PERIOD3 (PER3) was reported to present a weak association with chronotype. According to a recent model of cognition, the VLPFC plays a key role in higher cognitive control and is involved in complex neurobehavioral processes.