Communication between different cellular signaling systems has emerged as a common principle that enables cells to integrate a multitude of signals from its environment. Transactivation of the epidermal growth factor receptor (EGFR) represents the paradigm for cross-talk between G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). The recent identification of Zn2+-dependent metalloproteinases and transmembrane growth factor precursors as critical elements in GPCR-induced EGFR transactivation pathways has defined new components of a cellular communication network of rapidly increasing complexity. Further elucidation of the molecular details of the EGFR transactivation mechanism will provide new understanding of its relevance for normal physiological processes and their pathophysiological deviations.