Tumor resistance to agents targeting the Epidermal Growth Factor Receptor (EGFR) is common, and well recognised as a major challenge to successful clinical outcome, because patients often present with tumors that contain pre-existing intrinsic resistance mechanisms to current EGFR inhibitors, which ultimately has no therapeutic benefit. Furthermore, patients who initially respond to these therapies commonly relapse, presenting with new tumors that have acquired resistance to the original therapy. Substantial translational and clinical research has been undertaken in order to understand, and more importantly overcome, the molecular initiators of both intrinsic and acquired tumor resistance. However, despite a multitude of cost and effort in gaining greater understanding of the molecular mechanisms that drive tumor resistance, very little has translated into clinical practice and management of patients. 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 II) we will specifically focus on the resistance mechanisms mediated by alterations in substrates downstream of the EGFR and review other intracellular mechanisms that mediate both sensitivity and resistance outcomes to anti-EGFR agents.