Orexins (hypocretins) are novel neuropeptides released by some neurons identified in lateral hypothalamus. They are involved in the regulation of energy metabolism, neuroendocrine, sleep and waking. Recently, more and more evidence have shown that orexins play a key role in the stress and reward including drug addiction. The evidence was sumarized, showing that orexin neurons are well positioned to regulate stress-related neural systems, and orexin systems are involved in the physiological, neuroencocrine, psychological and behavioral process of stress. More recently, the role of orexins in stress-induced relapse of drug abuse has been established. All these evidence implicated that orexin system play a critical role in the process of stress, and their role in stress is dependent on the type of stress, their distribution and connection to other stress-related neurotransmitter systems.