Most immunology textbooks still promote the age-old idea that the sole function of mast cells is to mediate immunoglobulin E (IgE)-dependent responses in allergy and parasitic worm infections. But mast cells are extremely versatile cells and can be stimulated by numerous IgE-independent agonists, including pathogenassociated molecular pattern molecules (PAMPs), cytokines, hormones, and neuropeptides as well as through cellcell interactions. Depending on the activation mode, mast cells exhibit varied and ‘‘tunable’’responses, releasing unique arrays of preformed and newly synthesized pro-and/or anti-inflammatory mediators (Rao and Brown, 2008). This concept of a more multifunctional mast cell has been reinforced by a plethora of data documenting the contributions of these cells to protective immunity in viral and bacterial infections, in maintaining homeostasis and immunologic tolerance, and in exacerbating pathologic inflammation associated with cancer, heart disease, and autoimmunity (Rao and Brown, 2008). Collectively, these studies indicate that IgE-mediated responses may constitute only a small fraction of mast cells’ role in immunity.

However, data presented in a recent Immunity paper challenge this concept of a more versatile mast cell (Feyerabend et al., 2011). With a newly generated mast cell-deficient mouse strain, the authors fail to observe a role for mast cells in models of rheumatoid arthritis (RA) and multiple sclerosis (MS), diseases previously demonstrated to be mast cell dependent. They propose that the classic model systems used to assign mast cell activities in vivo have led to an overestimation of their roles in health and disease, an idea supported by Katz and Austen (2011) in their accompanying preview. Yet in making this argument, the authors ignore overwhelming evidence supporting the diverse functions of mast cells. Furthermore, their studies of experimental autoimmune encephalomyelitis (EAE), the