Mast cells (MCs), apart from their classic role in allergy, contribute to a number of biologic processes including wound healing. In particular, two aspects of their histologic distribution within the skin have attracted the attention of researchers to study their wound healing role; they represent up to 8% of the total number of cells within the dermis and their cutaneous versions are localized adjacent to the epidermis and the subdermal vasculature and nerves. At the onset of a cutaneous injury, the accumulation of MCs and release of proinflammatory and immunomodulatory mediators have been well documented. The role of MC-derived mediators has been investigated through the stages of wound healing including inflammation, proliferation, and remodeling. They contribute to hemostasis and clot formation by enhancing the expression of factor XIIIa in dermal dendrocytes through release of TNF-α, and contribute to clot stabilization. Keratinocytes, by secreting stem cell factor (SCF), recruit MCs to the site. MCs in return release inflammatory mediators, including predominantly histamine, VEGF, interleukin (IL)-6, and IL-8, that contribute to increase of endothelial permeability and vasodilation, and facilitate migration of inflammatory cells, mainly monocytes and neutrophils to the site of injury. MCs are capable of activating the fibroblasts and keratinocytes, the predominant cells involved in wound healing. MCs stimulate fibroblast proliferation during the proliferative phase via IL-4, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) to produce a new extracellular matrix (ECM). MC-derived mediators including fibroblast growth factor-2, VEGF, platelet-derived growth factor (PDGF), TGF-β, nerve growth factor (NGF), IL-4, and IL-8 contribute to neoangiogenesis, fibrinogenesis, or reepithelialization during the repair process. MC activation inhibition and targeting the MC-derived mediators are potential therapeutic strategies to improve wound healing through reduced inflammatory responses and scar formation.