Many studies have suggested an association between overexpression of receptor tyrosine kinases (RTKs) from the EGF receptor (or ErbB) family and breast cancer. The orphan RTK ErbB2/HER2/Neu is highly overexpressed in up to 30% of human breast cancer cases as a consequence of gene amplification. ErbB2/HER2/Neu can be activated by simple overexpression, and its signaling is thought to play an important role in initiation and progression of ErbB2-positive breast cancers. In support of this, ErbB2/HER2/Neu-targeted therapy (the Herceptin antibody) has proven valuable in many of these cases. Other studies also correlate EGF receptor (EGFR) expression with poor prognosis in breast cancer, but follow-up studies suggest that this association is much less robust than with ErbB2, and requires more careful analysis. A particular problem is that EGFR, unlike ErbB2/HER2/Neu, cannot be activated simply by overexpression, its signaling remaining growth factor-dependent under these conditions. It is therefore critical to analyze EGFR signaling activity itself, rather than simply EGFR expression, in order to establish causal links and to identify patients for ErbB-targeted therapies. This distinction between ErbB2/HER2/Neu and EGFR is satisfyingly explained by recent crystallographic studies of ErbB receptor family members that are reviewed here. These structures also provide new insight into how ErbB2/HER2/Neu-targeted and EGFR-targeted therapeutic agents function, and suggest approaches for the development of novel mechanism-based ErbB inhibitors.