Abnormal activation of the epidermal growth factor receptor (EGFR) and its homolog HER2 (Neu/ErbB2) has been associated with many human cancers, and monoclonal antibodies targeting EGFR and HER2 are effective anticancer therapies. Structural studies of these receptors and antibodies have revealed much about how they function. In this issue of Cancer Cell, Schmiedel et al. report structural and functional studies of the anti-EGFR monoclonal antibody Matuzumab. They show that Matuzumab binds and inhibits EGFR in a manner distinctive from that of other therapeutic anti-EGFR antibodies and suggest that combination therapies with Matuzumab and other antibodies may prove beneficial.