We study how cells respond to their microenvironments at the molecular level. Invariably, this response starts with engagement of membrane receptors, such as receptor tyrosine kinases (RTKs). RTKs associate in the plasma membrane and then engage cytoplasmic proteins to trigger signaling cascades which control cell growth, differentiation, and motility. The strength of the interactions, and the stoichiometry of the complexes control the outcome of these signaling cascades. We develop fluorescence-based methodologies that report on receptor interactions in the plasma membrane; they yield the association state of the receptors and the free energies of association. The enhanced capabilities provided by these methods have allowed us to broadly define the principles behind RTK activation. We have put forward a new model of RTK activation termed “the transition model” which captures the complexity of RTK signaling. The methodologies developed by us have further revealed a wide network of RTK interactions that can have a profound effect on function. We are now expanding the methodologies to study the interactions between membrane receptors and soluble adaptor proteins and thus, downstream signaling.