Melanocortin receptor-based drug discovery is particularly active in the field of neuroendocrine systems and is mostly related to food intake and novel obesity therapies. The immunomodulatory and anti-inflammatory effects of nonpeptidic, low molecular weight compounds activating the melanocortin-1 receptor (MC1R) provide a new principle for treating various types of inflammation, such as dermal, joint, and gastrointestinal, probably by virtue of the effects acting through modulation of proinflammatory and anti-inflammatory cytokines. Several reports demonstrate that alpha-MSH, for example, has anti-inflammatory effects in different models. The aim of our study was to design, synthesize, and characterize compounds that bind to and activate the MC1R in vitro. The binding affinities are submicromolar to this receptor, and activation of the receptor (cAMP assay) varies from full agonists to partial agonists as well as antagonists. In vivo, the compounds exert prominent anti-inflammatory effects, with efficacy in the same range as that of dexamethasone, for example. The potential advantages of MC1R-based anti-inflammatory effects versus glucocorticosteroids, for example, are that the latter, albeit exerting prominent anti-inflammatory effects, also have many side effects that most likely will not characterize an MC1R-based anti-inflammatory drug.