Mast cells are widely distributed in tissues, particularly near surfaces exposed to the environment. Mast cells can be activated to secrete diverse mediators and cytokines by IgE and specific Ag and many other stimuli, including products derived from either pathogens or the host during innate immune responses. Although mast cells are best known for their role in IgE-associated allergic disorders, mast cells can also exacerbate models of autoimmunity, enhance the sensitization and/or effector phases of certain cutaneous contact hypersensitivity responses, and increase inflammation and mortality during some severe bacterial infections. In other settings, however, mast cells can limit inflammation and tissue injury: mast cells promote host resistance in certain models of bacterial or parasite infection, limit pathology during some acquired immune responses to environmental Ag, including examples of severe contact hypersensitivity, and have adjuvant-like properties that can enhance the development of protective immunity against pathogens. These and other findings suggest that mast cells occupy a critical niche at the interface of innate and acquired immunity, where, depending on circumstances that remain to be fully understood, mast cells may function to perturb or help to restore homeostasis (or both), with consequences that can either promote health or contribute to disease.