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Over the past years, a holistic approach has been applied to the study of the field of receptor signaling, permitting the analysis of how the interaction between receptors and their cellular environment determines receptor function and the study of the role of these receptors, under both normal and pathophysiological conditions, in whole organisms. This has been facilitated by the development of high-resolution microscopy techniques, which allow single-molecule or spatiotemporal resolution, or both, of signaling processes at the cellular and organismal levels. Concurrently, the role of these signaling pathways can be tested in increasingly sophisticated murine disease models. Finally, computational approaches aid in predicting and understanding receptor behavior. The program of the Madrid meeting reflected this integrated approach, highlighting signaling by and dynamics and regulation of immune cell receptors, the T cell receptor and B cell receptor, and signaling by and regulation of G protein–coupled receptors.