An increasingly high occurrence of chronic pain in patients highlights the importance of fundamental research. The melanocortin-4 receptor (MC4R) regulation of pain has attracted much attention in recent years due to its high expression in the mammalian brain regions related to nociception and pain. This review is devoted to anatomic distribution of MC4R in the brain and interaction between MC4R and other pathways for pain modulation. The experimental evidence available at present had expanded our understanding of melanocortin-4 receptor regulation of pain. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.