Regulation of the Epidermal Growth Factor Receptor (EGFR) by its growth factor ligands is critical in many biological processes, including development and tissue maintenance and growth. Aberrant overexpression or activation by mutation of EGFR is associated with many human tumors. In these contexts, constitutive signaling can lead to cellular transformation and oncogenesis, thereby driving the cancer. The EGFR is the target of several existing or developing cancer therapies or immunotherapies, including monoclonal antibodies that prevent its activation. Activating mutations in cytoplasmic tyrosine kinase domain have been identified in many cancers, and have been the focus of mechanistic work. In this dissertation, I focus on the mode of oncogenic dysregulation by novel extracellular mechanisms. Extracellular oncogenic variants of EGFR include point mutations and alternative splice variants of EGFR. I find through biochemical analysis of the activating missense mutations in the extracellular region of EGFR that the soluble extracelluar region of EGFR (sEGFR) harboring these mutations bind ligands with elevated affinities. The dimerization energetics of these sEGFR mutants is not measurably altered, which suggests that additional interactions from the membrane and/or the intracellular region are important to this novel mode of extracellular oncogenic dysregulation of EGFR. I present preliminary progress towards the application of hydrogen/deuterium exchange coupled to mass spectrometry to analyze such allosteric (dys)regulation of the EGFR. In a second focus, I studied mechanisms of antibody targeting of EGFR. There are several monoclonal therapeutic antibodies that are in clinical development or use that target the EGFR/ErbB/HER family of receptor tyrosine kinases, including cetuximab/Erbitux™, panitumumab/Vectibix™, and necitumumab/Portrazza™, which all target EGFR, as well as trastuzumab/Herceptin™ and pertuzumab/Perjeta™, which target ErbB2/HER2. Unfortunately, as observed for most targeted therapies for cancer, resistance to these antibody therapies limits the duration of their effective treatment. Recent exome sequencing analyses of KRAS-WT colorectal cancer patients resistant to cetuximab treatment has identified epitope mutations as a mechanism of resistance. Whereas these mutated receptors bind cetuximab with dramatically decreased affinities, I report that they retain high affinity binding for necitumumab, a humanized IgG1 anti-EGFR antibody that shares the same epitope as cetuximab and panitumumab, and was recently FDA approved for squamous non-small cell lung carcinoma. I determined an X-ray crystal structure of the Fab fragment of necitumumab with the most commonly found resistance mutation—S492R (or S468R using the numbering scheme that starts at the beginning of the mature EGFR protein). This structure reveals a relatively hydrophobic cavity in the paratope of necitumumab that can accommodate the arginine at position S492/468 in the EGFR epitope. Further I find that other cetuximab and panitumumab resistance variants of EGFR are also permissive for necitumumab binding, suggesting significant plasticity in binding of necitumumab to EGFR. A survey of structures of therapeutic antibodies bound to their targets suggests that paratope shape may be an important property to consider in the selection of monoclonal antibodies in therapeutic strategies. Another mechanism of oncogenic dysregulation is the gene rearrangement of EGFR that results in EGFR variant III (EGFRvIII), an important target of many classes of immunotherapies for glioblastoma multiforme (GBM). I show in small angle X-ray scattering analyses of the ectodomain of EGFRvIII some evidence of structural flexibility in domain II that may be important for its documented transactivation of other receptor tyrosine kinases. I also report an X-ray crystal structure of the ectodomain of EGFRvIII in complex with the antigen binding or VHH domain of a camelid heavy-chain only antibody (HCAb), that has ~25-fold specificity for EGFRvIII compared to wild type EGFR. The structure reveals that the VHH gains specificity for EGFRvIII by targeting an epitope on domain IV that is sterically occluded in wild type EGFR by the intramolecular ‘tether’. This structure provides the direct evidence of dynamic uncoupling of the ‘tether’. My work corroborates the utility of the ‘tether’ as a source of antibody specificity for oncogenic EGFR, and is the first structural view of specific antibody targeting of an oncogenic EGFR variant.