The melanocortin system is probably the most complex neuroendocrine system known in vertebrates. Not only does it integrate different agonists encoded by a common precursor, the so-called proopiomelanocortin (Pomc), or non-Pomc agonists such as β-defensin, endogenous antagonists such as Asip (agouti-signalling protein) and Agrp (agouti-related protein) as well as five different receptors (Mcr), but also some accessory proteins that promote the functional expression or modify the pharmacological profile of Mcrs. The different duplications of the genome (R1, R2 and R3) together with some co-evolutionary and tandem duplication events have broadened the complexity of the system. According to this complexity, not only are evolutionary patterns controversial, but several hypotheses have attempted to explain the evolutionary relationships among members of the melanocortin system. In this review, we summarise the different evolutionary hypotheses given for the various melanocortin partners.