Mast cells are tissue-bound cells of the innate immune system which are well known for immunoglobuline (Ig)E-triggered degranulation in allergic reactions. More recently, an important role of mast cells has been described in chronic inflammatory and autoimmune disorders which are often associated with fibrosis or sclerosis. Innate immune receptors such as Fc-, toll-like- or NOD-like receptors stimuli can trigger mast cell degranulation and enhance immunological danger signals. Whereas fulminant degranulation of mast cell vesicles is observed in anaphylaxis, piecemeal degranulation or transgranulation are mechanisms for a slower release of their granula. A cocktail of cytokines, growth factors and proteoglycans is produced and stored in granula of mast cells. Mast cells are a substantial reservoir of both preformed inflammatory factors (i.e., TNF-alpha and IL-17) and factors that can trigger a profibrotic, Th-2-polarised inflammation (i.e., IL-4 and IL-10). In systemic sclerosis, mast cell vesicles are the main source of transforming growth factor (TGF)-beta. Cell-to-cell contact between mast cells and fibroblasts occurs in the affected tissue, supporting the hypothesis that transgranulation might be an important mechanism in fibrosis. The direct release of proteoglycans such as hyaluronic acid into the interstitial space is a further stimulus for matrix remodelling. Mast cell hyperactivity has also been demonstrated in primary fibrotic disorders such as lung, cardiac or renal fibrosis. The exact trigger for mast cell degranulation however is not known. Notwithstanding, at a very early time point of fibrosis, mast cell inhibition by stabilisers or blockage of the tyrosine kinase receptor c-kit by masitinib could be a therapeutic option.