Secretion from mast cells and basophils, two cells central to immediate hypersensitivity reactions, has characteristics that suggest the existence of intrinsic signal transduction processes that limit the extent of the cell's response. This process(es) has been termed desensitization. One goal of current research efforts is to determine the mechanisms used by mast cells and basophils to down-regulate an ongoing secretory reaction. Recent studies have indicated that, like secretion itself, the mechanisms of down-regulation or desensitization differ according to the mediator being studied. Thus, for human basophils, there appear to be distinct signaling pathways leading to the secretion of the three major classes of mediators -- granules contents, lipids, and cytokines -- and each pathway appears to have distinct down-regulatory processes. For an ongoing secretory reaction, the secretion of histamine and LTC4 are limited by a process that does not involve the earliest steps in activation, activation of the early tyrosine kinases, lyn and syk. These early events persist for long periods which more appropriately correspond to the regulation of cytokine secretion. Recent studies have also indicated that the process of desensitization is altered during stimulation in the absence of extracellular calcium, the traditional method of examining this process. These studies indicate that down-regulation studied in this manner is not dependent on any of the signaling events currently defined as being necessary for secretion. A variety of processes are discussed and potential mechanisms based on most recent studies using cell lines are explored.