Mast cells are innate immune cells that function as regulatory or effector cells and serve to amplify adaptive immunity. In adaptive immunity these cells function primarily through cell surface Fc receptors that bind immunoglobulin antibodies. The dysregulation of their adaptive role makes them central players in allergy and asthma. Upon encountering an allergen (antigen), which is recognized by immunoglobulin E (IgE) antibodies bound to the high affinity IgE receptor (FcepsilonRI) expressed on their cell surface, mast cells secrete both preformed and newly synthesized mediators of the allergic response. Blocking of these responses is an objective in therapeutic intervention of allergic diseases. Thus, understanding the mechanisms by which antigens elicit mast cell activation (via FcepsilonRI) holds promise toward identifying therapeutic targets. Here we review the most recent advances in understanding antigen-dependent mast cell activation. Specifically, we focus on the requirements for FcepsilonRI activation, the regulation of calcium responses, co-stimulatory signals in FcepsilonRI-mediated mast cell activation and function, and how genetics influences mast cell signaling and responses. These recent discoveries open new avenues of investigation with therapeutic potential.