Mast cells are crucial effector cells in allergic reactions, where IgE is the best known mechanism to trigger their degranulation and release of a vast array of allergic mediators. However, IgE is not the only component to stimulate these cells to degranulate, while mast cell activation can also result in differential release of mediators. There is a plethora of stimuli, such as IgG, complement components, TLR ligands, neuropeptides, cytokines, chemokines and other inflammatory products, that can directly trigger mast cell degranulation, cause selective release of mediators, and stimulate proliferation, differentiation and/or migration. Moreover, some of these stimuli have a synergic effect on the IgE-mediated mast cell activation. Because of the ability to respond to a large repertoire of stimuli, mast cells may act as a versatile cell in various physiological and pathological conditions. In this review, we discuss current knowledge on non-IgE stimuli for (human) mast cells.