This chapter focuses on α-melanocyte-stimulating hormone (α-MSH) and its known melanotropic activities within the framework of peptide hormone-receptor interactions. The development of MSH-based molecular probes, that is, superpotent agonists, radiolabeled analogs, photoaffinity derivatives, and melanotropin-macromolecular conjugates to evaluate the mechanism(s) of action of a-MSH has been an important hallmark in the progress of research on MSH receptors and signal transduction. Peptide hormones are physiologically active molecules important in a variety of endocrine, neuroregulatory, and other cellular processes. Evidence for such MSH receptors was first indicated by studies on covalent MSH-macromolecular complexes which would unlikely be transported across the plasma membrane. Future structure-activity studies utilizing such MSH radioreceptor assays are expected to have several applications in the examination of the molecular basis of MSH binding and signal transduction. Pharmacological characterization of receptors has generally focused on the objectives of demonstrating ligand specificity and quantitatively determining ligand affinities, saturability, and reversibility by the application of radiolabeled ligand derivatives.