ABSTRACT. The shape of a cell is an indicator of the health of the cell and tissues within the cells exist. For over a century the medical discipline of pathology has successfully used cell shape and tissue organization to diagnose disease states. My colleagues and I have been studying how the information in cell shape is decoded and have found that multiple mechanisms exist for information retrieval. Using analytical approaches and numerical simulations we studied how cell shape affects biochemical signaling across the plasma membrane. Mathematical analyses reveal transient accumulation of activated receptors that arise from local imbalance between reaction and diffusion of soluble ligands and receptors in the plane of the membrane. Numerical simulations show that transient microdomains of activated receptors amplify signals to downstream protein kinases. The model predictions have been experimentally validated for growth factor and G protein coupled receptors. In addition to modulating information flow through receptors for extracellular biochemical ligands, information from cell shape can be retrieved independently. Theoretical analyses, based on reaction/diffusion balance that is dependent on surface-to-volume relationships and optimal control theory, indicate that information from cell shape can be resolved from mechanical signals. β3-integrin signaling pathway communicates cell shape information in kidney podocytes and vascular smooth muscle cells. Differential proteomics and functional ablation assays indicate that β3-integrin uses the ezrin-radixin-moesin (ERM) family to transduce shape signals. We find that 3-D cell shape information regulates phenotype as defined by expression of proteins required for physiological function and their location to appropriate subcellular regions. Recent studies in vascular smooth muscle cells show that cell shape regulates organelle location, inter-organelle distances and differential distribution of receptors in the plasma membrane. Combination of these factors leads to the modulation of signals transduced by the M3 muscarinic receptor/Gq/ Phospholipase C-β pathway at the plasma membrane, amplifying Ca2+ dynamics in the cytoplasm and the nucleus as determined by increased activity of myosin light chain kinase in the cytoplasm and enhanced nuclear localization of the transcription factor NFAT. Thus acute physiological responses can be coupled to longer term transcriptional programs. Overall these observations provide insights into how cell shape can control physiological functions at the tissue level.