Hypothalamus is considered as an important brain region regulating natural rewards. Orexin, a neuropeptide specifically expressed in hypothalamus, arrests investigators much attention for its function in drug rewards. Orexin neurons in different brain regions exert different roles in regulating reward and motivation in the addiction research: orexin neurons in perifornical area (PFA) and dorsomedial hypothalamus (DMH) are mainly concerned with activating stress system, while orexin neurons in lateral hypothalamus participate in mediating reward-related behavior through activating brain circuitry involved in reward learning. The orexin system may therefore represent a target for preventing relapse to drug seeking during protracted abstinence. And targeting orexin receptors may provide new therapeutic strategies to treat addiction.