Tissue mast cells play a central role in immediate hypersensitivity reactions. The clinical manifestations of these reactions appear to be dependent, in large part, on the anatomic location of the stimulated mast cells and the type of mediators released. In vivo and in vitro studies indicate that the tissues in which mast cells reside may greatly influence their biochemical composition, expression of surface receptors, and response to potential stimuli. Although all human mast cells in different organs store similar concentrations of histamine, heparin, and tryptase, cutaneous mast cells appear to be the predominant source of mast cell-derived chymase. Furthermore, at the time of stimulation, human skin mast cells predominantly form PGD2, whereas lung and intestinal mast cells generate LTB4, LTC4, and PGD2. Functional studies indicate that human cutaneous mast cells differ from human lung, heart, and intestinal mast cells. Skin mast cells are responsive to a variety of immunologic and nonimmunologic stimuli in vitro, whereas human pulmonary, cardiac, and intestinal mast cells are relatively refractory to many of these stimulatory signals. Taken together, these observations indicate that mast cells may assume different, and possibly specialized, functions within a specific tissue. Such site-to-site variation potentially could have important clinical significance, to the extent that information gained from mast cells in one organ may not be applicable to a mast cell population in a different tissue. Furthermore, these differences among human mast cells may not be confined to their biochemical composition and responses to various stimuli, but also may extend to the effectiveness of different anti-allergic preparations. Therefore, these observations underscore the importance of continued detailed investigation of human mast cells from different anatomic sites.