The mechanism of melanocyte-stimulating hormone (MSH) action has been investigated mainly with extensive structure-activity studies using various assays, such as melanophore and melanoma cell assays or behavioral tests. Peptides that retain high biological activity in spite of the modifications produced by the labels are a prerequisite for the study of MSH receptors with labeled MSH derivatives. MSH receptors on melanocytes, melanoma cells, in the brain, and in other tissues, occur in very small numbers and, hence, can only be studied with biologically active MSH derivatives of high specific radioactivity. Several tritiated α-MSH derivatives and one tritiated MCH analog have been described in the literature. The most important factor in the preparation of biologically active radioiodinated MSH is the purification procedure. Instead of using radioactive labels, fluorescent groups, or macromolecules, or combinations thereof have been tested for MSH receptor studies. Some studies investigate α-MSH derivatives containing SH-sensitive affinity groups for receptor labeling.