In this article, we have described studies that have demonstrated that mast cells can be activated as a consequence of adaptive and innate immune reactions and that these responses can be modified by ligands for other receptors expressed on the surface of mast cells. These various stimuli differentially activate multiple signaling pathways within the mast cells required for the generation and/or release of inflammatory mediators. Thus, the composition of the suite of mediators released and the physiologic ramifications of these responses are dependent on the stimuli and the microenvironment in which the mast cells are activated. Knowledge of the different signaling molecules used by cell surface receptors may allow selective pharmacologic targeting such that inhibiting the adverse effects of mast cell activation can be achieved without influencing the beneficial effects of mast cell activation. The exact interconnections between the signaling pathways initiated by the surface receptors described in this article remain to be completely worked out; thus, this remains a topic for future investigation.