Mast cells are well known for their role in type I hypersensitivity. However, their role in the immune system as well as their pathophysiological role in other diseases is underacknowledged. The role of mast cells in inflammatory bowel disease, allergic contact dermatitis and asthma is illustrated in this review. The contribution of mast cell activation in these diseases is controversial and two alternative means are proposed: activation via stress response pathways and immunoglobulin-free light chains. Activation of the mast cells leads to release of preformed mediators and to generation of other potent biological substances that have both physiological and pathophysiological effects. The role of these mediators in the aforementioned diseases is also outlined in this review. When the roles of mast cells are better understood, drugs specifically targeting mast cells may be developed to effectively treat a wide range of diseases.