Allergic diseases have reached epidemic proportions affecting more than 30% of the world population. Central players in the allergic and inflammatory reactions are the mast cells, cells of the immune system, that are packed with secretory granules in which inflammatory mediators, such as histamine, are stored. Allergy involves the activation and subsequent degranulation of mast cells. Activation involves binding of allergens to cell-bound Immunoglobulin E (IgE)  class antibodies, specific for a wide range of allergens, or direct activation by neurotransmitters, drugs, pathogens or interactions with neighbouring cells. Through complex cellular interaction networks, mast cells participate in allergy, neurogenic inflammation and many chronic inflammatory diseases, including autoimmune diseases, neurodegenerative diseases and cancer.  A major challenge in allergy treatment is to understand the underlying mechanisms of mast cell degranulation and identify the critical players in this process.