Mast cells are central mediators of allergic diseases. Their involvement in allergic reactions is largely dependent on activation through the specific receptor for IgE (Fc epsilon RI). Cross-linking of Fc epsilon RI on mast cells initiates a cascade of signaling events that eventually results in degranulation, cytokine/chemokine production, and leukotriene release, contributing to allergic symptomology. Because of the importance of IgE in allergy, much focus has been placed on deciphering the signaling events that take place downstream of Fc epsilon RI. Studies have identified spleen tyrosine kinase as a key proximal regulator of Fc epsilon RI-mediated signaling. In this review, we discuss the multiple pathways that diverge from spleen tyrosine kinase with emphasis on the role of adapter molecules to orchestrate these signaling events. Understanding the molecular mechanisms underlying mast cell activation ideally will provide insights into the development of novel therapeutics to control allergic disease.