This chapter reviews the structure-activity relationships in cyclic melanotropins and their inferences for further rational design of melanotropins, the structure-activity relationships of relevant selected linear melanotropins. The designation melanotropin has been applied to a large number of structurally similar peptides. A careful examination of the structure-activity relationships in these linear analogs and application of rational design techniques led to the preparation of a series of cyclic analogs of α-melanophore-stimulating hormone (α-MSH), many of which possess greater biological potency than their linear counterparts in the classical in vitro frog skin bioassay. Earlier structure-function studies of α-MSH have shown that the stereochemistry of the amino acid in the seven position of α-MSH has dramatic effects on the potency of the peptide. The in vitro biological assays allow quantitative measurements of the potency of melanotropins over a large dosage range. The contribution of the N-terminal tripeptide in α-MSH to the overall potency of the molecule has been examined extensively in linear analogs.