Mast cells often represent one of the first cells of the immune system to interact with environmental antigens, invading pathogens or environmentally-derived toxins. Mast cells also can undergo alterations in phenotype, anatomic distribution and numbers during innate or adaptive immune responses. In addition to their well-known roles as effector cells during IgE- and antigen-induced allergic reactions, mast cells can be activated by many other signals, including some that are derived directly from pathogens or which are generated during innate or adaptive immune responses. Mast cells also express many costimulatory molecules with immunoregulatory activities and can secrete many products that can positively or negatively regulate immune responses. In this chapter, we describe mouse models used for analyzing mast-cell function in vivo and illustrate how such models have been used to identify positive or negative immunomodulatory roles for mast cells during specific innate or adaptive immune responses. We also briefly describe some of the mast-cell functions, products and surface receptors that have the potential to permit mast cells to promote or suppress immune responses that can either enhance host defense or contribute to disease.