The skin is a target organ and source for proopiomelanocortin (POMC)-derived peptides, such as alpha-melanocyte-stimulating hormone (alpha-MSH), which acts by binding to melanocortin receptors (MC-Rs). Recent progress in our understanding of the cutaneous POMC system has demonstrated that human dermal fibroblasts (HDFs) are a novel target for alpha-MSH. MC-1R is expressed by HDFs in vitro and in situ. MC-1R expression is also detectable in human connective tissue sheath fibroblasts (CTSFs) and in dermal papilla cells (DPCs) of the hair follicle, the latter concomitantly expressing MC-1R and MC-4R in vitro and in situ. Both HDFs and DPCs are capable of generating POMC-derived peptides, although cell-specific differences exist in the expression of prohormone convertases and the amounts of POMC-derived peptides generated. Functional studies have shown that alpha-MSH exerts anti-inflammatory actions in human fibroblastic skin cells by suppressing interleukin-1 (IL-1)-induced IL-8 production, activation of the transcription factor activator protein-1 (AP-1) and induction of intercellular adhesion molecule-1 by interferon-alpha. In addition, alpha-MSH antagonizes the effect of transforming growth factor-beta1 (TGF-beta1) on collagen synthesis in HDFs in vitro and exerts antifibrogenic activity in a mouse model of cutaneous fibrosis. These findings indicate that fibroblastic cells participate in the cutaneous POMC system in which alpha-MSH appears to act as a modulator of inflammatory and fibrogenic responses. The biological activities of alpha-MSH in fibroblastic cells of the skin point towards novel clues in our understanding of the pathophysiology of fibrotic skin disorders and inflammatory diseases of the hair follicle and, finally, suggest innovative therapeutic options for the treatment of these conditions.