This chapter presents results from studies showing strong evidence for pronounced heritability of waking and rapid eye movement (REM) and non-REM sleep electroencephalographic (EEG) activity. Genes regulate the expression and function of the neurobiological systems that modulate sleep and wakefulness. The most commonly employed method for identifying genes involved in some aspect of physiological or behavioral regulation is the candidate gene approach. In this approach, individuals with genetic polymorphisms thought to be involved in sleep-wake regulation or neurobehavioral vulnerability to sleep loss are subjected to sleep loss in the laboratory, and neurobehavioral measures are assessed throughout. The chapter determines whether functional polymorphisms of the catechol-O-methyltransferase (COMT) gene moderate responsivity to other psychostimulants that also act via dopaminergic signaling. Genetic variations also appear to control individual responsivity to stimulants. Evidence indicates that the COMT Val158Met polymorphism controls individual responsivity to the stimulant modafinil during sleep loss.