While inflammatory processes, tissue injury, and repair are normally locally balanced, continuing high levels of these phenomena can result in overt fibrosis. Enhanced numbers of inflammatory cells, mainly mast cells and eosinophils, are well known to occur in several fibrotic conditions such as scleroderma and scleroderma-like diseases, physiological and pathological wound healing, Crohn's disease, chronic graft-versus-host disease (cGVHD), pulmonary and hepatic fibrosis, endomyocardial fibrosis, and sight-threatening disease. The fibroblast is the target cell in tissue remodeling. Usually, the addition of mast cells or eosinophils to fibroblast monolayers results in an increase of their proliferation and, according to the type of fibroblast, may also be accompanied by an enhancement of collagen synthesis. Mast cells and eosinophils release a wide spectrum of biologically active compounds that, when added to fibroblasts, can exhibit both fibrogenic and fibrolytic activities. Among the various mast cell mediators, histamine seems to be partially responsible for the enhanced fibroblast proliferation, while tryptase and chymase appear to play a role in modulating collagenase activity. Most of the cytokines produced by mast cells (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, GM-CSF, TNF-α, TGF-β) and by eosinophils (GM-CSF, IL-6, IL-2, IL-4, TNF-α, TGF-β) were shown to modulate fibroblast proliferation and collagen synthesis. This review, based on studies from our laboratory as well as from others, provides strong evidence for the direct involvement of mast cells and eosinophils in tissue remodeling in different anatomical locations. Since cure, or preferably prevention, of fibrosis is still not possible, it is of primary importance to define which mast cells and eosinophil mediators are directly involved in the modulation of fibroblast properties, as well as their cellular and subcellular mechanisms of activity, with the ultimate goal of finding new therapeutic targets for the resolution of fibrotic diseases.