Data suggest that neither our current understanding of the function and signalling of epidermal growth factor receptor (EGFR), nor measurements of receptor expression are reliably predictive of therapeutic responses to EGFR inhibitors. The time has now come to consider whether such poor correlation between receptor expression and clinical response is caused by poor assays or by more fundamental issues relating to the in-vivo function of EGFR. Revisiting some of the early findings of the biology of EGFR function and understanding the limitations of immunohistochemistry as a quantitative technique might provide some clues. However, we still have a lot to learn about this receptor, its many ligands, and its binding partners in normal physiology and disease.