This chapter discusses the orexins and opioids as an important part of the neural network that operates to maintain natural feeding behavior. Behavioral and neurobiological evidence demonstrates that orexins and opioids are an important part of the neural network that operates to maintain natural feeding behavior. Orexins and opioids consistently stimulate food intake and interact to elicit feeding; blockade of one affects the response to the other. The strength of the feeding response for each depends on the brain site of administration. Together, these indicate a network model of feeding behavior in which both orexins and opioids participate. The chapter also discusses the interaction between opioids and orexins. Orexin neurons may also mediate reward-based feeding via its interaction with opioids. Orexin A (OxA)-induced feeding is dependent on functional opioid pathways because central opioid antagonist injections block OxAinduced feeding. Also, OxA selectively enhances high-fat consumption when animals are given the choice of high- and low-fat diets.