-Melanocyte-stimulating hormone (-MSH) is a tridecapeptide derived from the proopiomelanocortin. Many studies over the last years have provided evidence that -MSH has potent protective and anti-inflammatory effects. These effects can be elicited via centrally expressed melanocortin receptors which orchestrate descending neurogenic anti- inflammatory pathways. -MSH can also exert anti-inflammatory and protective effects on cells of the immune system and on peripheral non-immune cell types expressing melanocortin receptors. At the molecular level, -MSH affects various pathways implicated in regulation of inflammation and protection, i. e. NF-B activation, expression of adhesion molecules and chemokine receptors, production of proinflammatory cytokines and mediators, interleukin (IL)-10 synthesis, T cell proliferation and activity, inflammatory cell migration, expression of anti-oxidative enzymes and apoptosis. The anti-inflammatory effects of -MSH have been validated in animal models of experimentally-induced fever, irritant and allergic contact dermatitis, vasculitis and fibrosis, in ocular, gastrointestinal, brain and allergic airway inflammation, and arthritis but also in models of organ injury. One obstacle limiting the use of -MSH in inflammatory disorders is its pigmentary effect. Due to its preserved anti- inflammatory effect but lack of pigmentary action, the C-terminal tripeptide of -MSH, KPV, has been delineated as an alternative for anti-inflammatory therapy. KdPT, a derivative of KPV corresponding to amino acid 193–195 of IL-1, is also emerging as a tripeptide with anti- inflammatory effects. The physiochemical properties and expected low costs of production render both agents suitable for the future treatment of immune-mediated inflammatory skin and bowel disease, fibrosis, allergic and inflammatory lung disease, ocular inflammation, and arthritis.