Abstract: To better understand the neurobiology of sleep disorders, detailed understanding of circadian and homeostatic sleep-wake regulation in healthy volunteers is mandatory. Sleep physiology and the repercussions of experimentally induced sleep deprivation on sleep and waking electroencephalogram (EEG), vigilance and subjective state are highly variable, even in healthy individuals. Accumulating evidence suggests that many aspects of normal sleep-wake regulation are at least in part genetically controlled. Current heritability estimates of sleep phenotypes vary between approximately 20-40 % for habitual sleep duration, to over 90 % for the spectral characteristics of the EEG in nonREM sleep. The molecular
mechanisms underlying the trait-like, inter-individual variation are virtually unknown, and the human genetics of
normal sleep is only at the beginning of being explored. The first studies identified distinct polymorphisms in genes contributing to the endogenous circadian clock and neurochemical systems previously implicated in sleep-wake regulation, to modulate sleep architecture and sleep EEG, vulnerability to sleep loss, and subjective and objective effects of caffeine on sleep. These insights are reviewed here. They disclose molecular mechanisms contributing to normal sleep-wake regulation in humans, and have potentially important implications for the neurobiology of sleep-wake disorders and their pharmacological treatment.