Although a role for hypocretin/orexin (HCT/ORX) in sleep/wakefulness and arousal is widely recognized, other actions, not necessarily related to sleep, have been identified. Neurons producing the peptides project to brain sites known to be important in neuroendocrine and autonomic function, as well as appetite regulation. There is consensus that HCT/ORX plays a role in the regulation of cardiovascular function via its effects on sympathetic nervous activity, and the reported pharmacologic effects have been demonstrated to be physiologically relevant. Equally provocative are the actions of these peptides in the hypothalamus and pituitary gland to regulate reproductive and stress hormone secretion. While HCT/ORX are less potent stimulators of food intake than other hypothalamic peptides, HCT/ORX may play an integral role in the organization of hunger and satiation behaviors because of their interaction with those other peptides. In fact recent discoveries of interactions of HCT/ORX with peptides such as corticotropin releasing hormone and neuropeptide Y, as well as with aminergic neurotransmitter systems, are now defining the cellular and molecular mechanisms by which these potent neuropeptides act and promise insight into their physiologic relevance in a variety of non-sleep related behaviors and other homeostatic mechanisms.