The development of new therapeutics for sleep disorders is increasingly dependent upon understanding the basic brain circuitry that underlies sleep–wake regulation, and how it may be pharmacologically manipulated. In this review, we consider the pathophysiological basis of major sleep disorders that often are seen by neurologists, including excessive daytime sleepiness, insomnia, narcolepsy, rapid eye movement sleep behavior disorder, and restless legs syndrome, as well as circadian disorders, and we review the current and potential future therapeutic approaches. Ann Neurol 2013;74:435–440