Regulation of energy balance is extremely complex, and involves multiple systems of hormones, neurotransmitters, receptors, and intracellular signals. As data have accumulated over the last two decades, the CNS melanocortin system is now identified as a prominent integrative network of energy balance controls in the mammalian brain. Here, we will review findings from rat and mouse models, which have provided an important framework in which to study melanocortin function. Perhaps most importantly, this review attempts for the first time to summarize recent advances in our understanding of the intracellular signaling pathways thought to mediate the action of melanocortin neurons and peptides in control of longterm energy balance. Special attention will be paid to the roles of MC4R/MC3R, as well as downstream neurotransmitters within forebrain and hindbrain structures that illustrate the distributed control of melanocortin signaling in energy balance. In addition, distinctions and controversy between rodent species will be discussed.