Epidermal growth factor receptor (EGFR) and its most common extracellular mutant, EGFRvIII, are important therapeutic targets in multiple cancer types. A number of monoclonal antibodies and small-molecule inhibitors against these receptors are now used for anticancer treatments. New insights into the structure and function of these receptors illustrate how they can be targeted in novel ways, with expected improvements in the therapeutic efficacy. Monoclonal antibody 806 (mAb806) is an antibody that targets a conformationally exposed epitope of wild-type EGFR when it is overexpressed on tumor cells or in the presence of oncogenic mutations such as EGFRvIII. The mechanism of action of mAb806, which allows for EGFR inhibition without normal tissue toxicity, creates opportunities for combination therapy and strongly suggests mAb806 will be a superior targeted delivery system for antitumor agents. Targeting of the epitope for mAb806 also appears to be an improved strategy to inhibit tumors that express EGFRvIII. This concept of conformational epitope targeting by antibodies reflects an underlying interplay between the structure and biology of different conformational forms of the EGFR family.