Eating, drinking and taking addictive drugs are the behaviors driven by motivation. They are regulated by neural networks such as the mammalian central melanocortin (MC) system and mesolimbic dopamine (DA) system. The MC system is referred as a collection of central nervous system (CNS) circuits, that include the neurons expressing proopiomelanocortin (POMC) or agouti gene–related protein (AgRP) locating in the arcuate nucleus, the brainstem POMC neurons originating in the commissural nucleus of the solitary tract, and the downstream targets of the POMC and AgRP neurons expressing the melanocortin receptors (MCRs). In the CNS, melanocortin peptides synthetized by POMC neurons are the agonists of the MCRs, while AgRP from AgRP neurons is a high-affinity antagonist to those receptors. The MC system plays a crucial role in regulating body energy homeostasis and multiple processes, such as food intake and reward-associated behaviors, through a certain pattern of cooperation between the POMC and AgRP neurons. The ventral tegmental area (VTA) is another key brain area in modulating reward-associated behaviors. There is a clearly anatomical association between the MC system and the VTA region, that the POMC and AgRP neurons in the ARC have direct projections on the DA neurons in the VTA. Thus, clear presentation of how the POMC and AgRP neurons and the DA system mutually mediate rewarding-associated behaviors may contribute to better understanding some abnormal reward-taking behaviors, such as drug addiction. The previous studies have shown that DA system is a common target for different addictive drugs, direct or indirect, as well as both acute and chronic drug exposure can alter the function of the POMC and AgRP neurons. Additive humans and animals show uncontrollably drug-taking behavior, being analogue to the individuals taking food under a hunger condition. Here, we hypothesize that drug addiction may result from the dysfunction the MC system (especially POMC and AgRP neurons). In other words, the functional balance between the MC and DA systems is disrupted by addictive drugs. This review firstly summarizes how the MC and DA systems collectively govern feeding behavior, and then presents what changes happen in the MC system following the drug use, as well as raises the potential mechanism underlying altered function of the MC system after repeated hyperactivation of DA pathway by addictive drugs.