Mast cells are often discussed to play an important role in the tissue fibrotic process, because increased numbers of mast cells are found in the fibrous lesions. Recent evidence has revealed that mast cells are a rich source of cytokines or mediators, which are supposed to play a crucial role in altering the environmental extracellular matrix, leading to fibrosis. Dermatofibromas (DFs) are benign tumors histologically characterized by local fibroblast proliferation. It has been demonstrated that multiple DFs occur in patients with autoimmune diseases or under immunosuppressive therapy, implying that DFs are reactive tumors, rather than true neoplasms, at least in one aspect. Increased numbers of mast cells are also found in both solitary and multiple DFs, in particular in the layers between the DF lesion and the overlying epidermis. The presence of mast cells could be significant in the induction of several histopathologic changes, including acanthosis of the overlying epidermis, basal melanosis, and possibly mononuclear cell recruitment, in DF. Further elucidation of the role of mast cells may lend support to the understanding of the mechanism of DF.