Mol Syst Biol. 2: 2006.0006 When you search PubMed for ‘EGF receptor’ (EGFR), the database returns more than 5000 hits. This is not entirely surprising given the receptor's eminent role in cancer biology. However, it is truly surprising that two recent papers published by the groups of Gavin MacBeath and Matthias Mann add a whole new dimension to the problem of EGFR signaling. They do that by using protein microarray and quantitative proteomics technologies to comprehensively and quantitatively identify proteins associated with the cytosolic domains of the human EGFR family (Jones et al , 2005; Schulze et al , 2005). This family of membrane receptors consists of four different proteins called EGFR/ErbB1/HER1, ErbB2/Neu/HER2, ErbB3/HER3, and ErbB4/HER4. Under normal physiological conditions, the ErbB receptors play crucial roles in propagating signals regulating cell proliferation, differentiation, motility, and apoptosis (Holbro and Hynes, 2004). They are activated by ligand binding, which leads to homo‐ or heterodimerization followed by trans‐phosphorylation of specific tyrosine residues. These phosphorylated tyrosines, in turn, provide recognition sites for cytoplasmic proteins, which link ErbB receptors to downstream signaling transduction cascades such as the MAP kinase pathway. Among all ErbB family members, EGFR and ErbB4 are fully functional receptor tyrosine kinases, whereas ErbB2 does not …