Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on hypocretin physiology. Monkeys were given the sleep-inducing γ-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid hypocretin-1 concentrations. Furthermore, hypocretin neurons do not seem to respond to an ‘effort’ to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.