Src family protein tyrosine kinases (SrcPTK) play a central role in immunoglobulin E (IgE)-mediated activation of mast cells. Functional coupling of the high-affinity IgE receptor (FcepsilonRI) is initiated by the SrcPTK family member, Lyn, through an antigen aggregation-dependent transphosphorylation. Because Lyn is the 'initiating' kinase, an essential role in mast cell effector function was conferred. Recent studies challenge this view. Evidence demonstrating that Lyn kinase is dispensable for mast cell degranulation is now available. In contrast, another SrcPTK family member, Fyn, is required for degranulation and cytokine production. New studies, on mast cells expressing FcepsilonRIbeta ITAM mutants, show that the loss of Lyn interaction with FcepsilonRI has only a modest inhibitory effect on mast cell degranulation and an enhancing effect on lymphokine production, although many of the biochemical signals (including FcepsilonRI phosphorylation) were significantly impaired. In vivo studies on Lyn-null mice also demonstrated that this kinase is a negative regulator of IgE production and anaphylaxis, whereas Fyn kinase is required for anaphylaxis but not for IgE production. Collectively, these studies argue that sustained Lyn kinase activity negatively regulates mast cell responses. This suggests the possible existence of Lyn polymorphisms that may contribute in allergic disease.