The melanocortin (MC) system is composed of different peptides centrally produced by proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (N.Arc) and the medulla. These peptides act through five subtypes of melanocortin receptors (MCRs) that belong to the family of seven-transmembrane G-protein-coupled receptors that are coupled through Gαs signaling pathways. MC3R and MC4R are the predominant MCR subtypes in the brain, and they are widely expressed in brain regions thought to modulate drug self-administration, including the nucleus accumbens, the hypothalamus, and the ventral tegmental area. The MC system is unique in terms of having an endogenous antagonist/inverse agonist, agouti-related protein (AgRP), also produces in the N.Arc and secreted in terminals expressing MCRs. There is a large body of research showing the role of the MC and AgRP systems in neurobiological responses to drugs of abuse, in particular, neurobiological responses to ethanol. In this chapter, we discuss the most recent evidence that supports the role of the MC/AgRP systems in modulating neurobiological responses to drugs of abuse, with a focus on ethanol consumption.