This chapter discusses the use of melanophores as it relates to one screening method, combinatorial or otherwise, but also to present information that facilitate adaptation and development of new procedures and approaches. “Combinatorial synthesis” describes methods for simultaneously generating large numbers of related molecules. The history of pharmacology would be incomplete without mention of melanophores and their impact on the fields of drug discovery and development. The striking color changes that occur in various fish, frog, reptile, and invertebrate species stand in contrast to the gradual modulation of skin tone seen in humans. Investigation of animal color change has a long history intertwined with that of basic neuroscience and endocrinology. Cultured melanophores provide a rapid and inexpensive way to test compounds for functional interactions with endogenous and recombinant seven-transmembrane G protein-linked receptors. Screening ligands against receptors endogenous to frog melanophores may not always give reliable indications of how the same compounds will behave at human receptors.