The epidermal growth factor receptor (EGFR; also referred to as HER1 or ERBB1), is a member of the type 1 receptor tyrosine kinase family known as the ERBB family. Comprising 4 members-ERBB1, ERBB2 (also known as HER2), ERBB3 (HER3), and ERBB4 (HER4)-these receptors play a principal role in allowing cells to integrate and respond correctly to diverse external stimuli, ranging from soluble endocrine and paracrine factors to signaling molecules on neighboring cells. The cell must interpret these extracellular signals to produce an appropriate developmental or proliferative response, and aberrant activation of the kinase activity of these receptors, particularly EGFR and ERBB2, is important in the development and progression of human cancer. Given its roles in signal transduction and development of the malignant phenotype, EGFR has emerged as a critical target for therapeutic development against various forms of cancer. This review focuses on the current therapeutic approaches directed against EGFR, the emerging challenges of EGFR therapy resistance, and how our increasing knowledge of EGFR biology is driving more targeted or alternative approaches to cancer therapies.