Clustering of the high-affinity receptor for immunoglobulin E (FcεRI) through the interaction of receptor-bound immunoglobulin E (IgE) antibodies with their cognate antigen is required to couple IgE antibody production to cellular responses and physiological consequences. IgE-induced responses through FcεRI are well known to defend the host against certain infectious agents and to lead to unwanted allergic responses to normally innocuous substances. However, the cellular and/or physiological response of individuals that produce IgE antibodies may be markedly different and such antibodies (even to the same antigenic epitope) can differ in their antigen-binding affinity. How affinity variation in the interaction of FcεRI-bound IgE antibodies with antigen is interpreted into cellular responses and how the local environment may influence these responses is of interest. In this chapter, we focus on recent advances that begin to unravel how FcεRI distinguishes differences in the affinity of IgE-antigen interactions and how such discrimination along with surrounding environmental stimuli can shape the (patho) physiological response.