A series of recent publications have finally provided clues to the molecular and genetic bases of sleep. A paper by Jones et al. in this issue (see 1062 and 983) reports that human Advanced Sleep Phase Syndrome is a inheritable genetic condition. Two recent papers described the first genes associated with narcolepsy, a debilitating sleep disorder. In the 6 August issue of Cell, Lin et al. identified a mutation in the gene encoding the orexin receptor 2 (Hcrtr2) as the cause of narcolepsy in Doberman pinschers. Then, in the 20 August issue of Cell, Manashi Yanagisawa's group reported that deletion of the Hcrtr2 ligand, orexin, causes a phenotype in mice that is remarkably similar to human narcolepsy. Orexins are neuroexcitatory peptides that are localized to synaptic vesicles of neurons in the lateral hypothalamus. They were initially believed to be involved in energy balance and control of feeding, but subsequent studies, including these two, suggest a broader role for orexins as major neuromodulators of sleep. Human narcolepsy is usually treated with amphetamine-like stimulants to control daytime sleepiness, and antidepressants to control REM sleep abnormailites. These studies suggest that orexins, or drugs that affect orexin function, may offer new therapeutic approaches for narcolepsy and other sleep disorders.