Energy intake and expenditure are regulated by a complex network of neurochemical systems. The results of numerous studies have provided information about receptors involved, the sites of action within the brain and interactions between various systems, including opioid and cannabinoid, in regulation of energy balance. This review summarizes our present knowledge on the opioid and cannabinoid system appetite and satiety pathways. The involvement of the three main types of opioid receptors (MOR, DOR and KOR) and CB1 cannabinoid receptor, as well as the endogenous ligands of these receptors in food intake is documented. Finally, the use of opioid-cannabinoid system interactions as a new approach in the search for the next generation therapeutics controlling food intake disorders is discussed.