Since its discovery several decades ago, the Epidermal Growth Factor Receptor (EGFR) has become one of the most extensively studies receptor tyrosine kinases. However, despite continued insight into the cancer promoting properties of the EGFR and its downstream signalling substrates, clinical use of agents targeting the EGFR continue to yield modest outcomes. Clinically, approved anti-EGFR therapeutics can successfully inhibit receptor activation. However major tumour regression is observed in only 10-30% of advanced unselected cancer patients, with most patients showing no therapeutic benefit. Furthermore, those who initially respond commonly relapse presenting with reoccurrence of tumours that are frequently resistant to the original therapy. In addition, the standard course of treatment of such agents is estimated to cost between “US $15,000-80,000/patient” for an improved overall survival of only 1-2 months. Therefore, it is both medically and financially critical to determine the true molecular mechanisms of tumour resistance, and how it can be overcome. In these 2 back-to-back chapters, we will provide an overview of the progress made in targeting the EGFR and discuss the challenges presented by the numerous molecular mechanisms currently identified, leading to overall refractory outcomes to anti-EGFR therapeutics. In this chapter (Part I) we will specifically focus on the resistance mechanisms driven by alterations in ligand and receptors of the EGFR family and cross-talk between EGFR receptors and non-EGFR family members.