The relevance of opioids in reward processes leading to addictive behavior such as self-administration of opioids and drugs of abuse including nicotine and alcohol is widely recognized. Data gleaned in recent years have uncovered the importance of the endogenous opioid system modulating feeding behavior and other parameters that are crucial for the regulation of energy balance in both prelinical and clinical settings. The effects of endogenous opioid tone in food intake appears to be exerted by the three main families of opioid receptors. Data obtained from transgenic knockout mice for the different receptors subtypes indicates that the complete lack of MOR and KOR causes important alterations in energy balance, particularly when mice are fed on fat-enriched diets . Administration of selective μ-agonists into the NAcc of rodents induces feeding even in satiated animals, while administration of μ-antagonists reduces food intake. Using pharmacological and gene silencing approaches, it was recently shown that ghrelin utilizes a hypothalamic κ-opioid receptor (KOR) pathway to increase food intake in rats. Pharmacological blockade of KOR decreases the acute orexigenic effect of ghrelin. Inhibition of KOR expression in the hypothalamic arcuate nucleus is sufficient to blunt ghrelin-induced food intake. By contrast, the specific inhibition of KOR expression in the ventral tegmental area does not affect central ghrelin-induced feeding. This new pathway is independent of ghrelin-induced AMP-activated protein kinase activation, but modulates the levels of the transcription factors and orexigenic neuropeptides triggered by ghrelin to finally stimulate feeding. These data implicate hypothalamic KOR signaling in the orexigenic action of ghrelin. Whether other orexigenic signals act through this pathway or whether this effect is specific for ghrelin is under investigation.