Human epidermal growth factor receptor (EGFR), HER, targeting has formed the basis of extensive and growing drug development programs in various companies. However, receptor biology is often poorly explained and confusing. The HER family of four naturally occurring receptors and one tumor-specific mutant can activate signaling via a complex and sophisticated range of mechanisms, which we are only beginning to understand. HER1/EGFR downstream signaling can lead to tumor growth and development via a host of processes, including enhanced cellular proliferation, survival, and metastasis. A range of potential therapeutic targets exists within the HER signaling system, both inside and outside the cell. Monoclonal antibodies and tyrosine kinase inhibitors, acting extracellularly and intracellularly, respectively, comprise two classes of agents most advanced in clinical development or already available for use. Despite promising single-agent activity in chemotherapy-resistant patients with non-small cell lung cancer (NSCLC), disappointing results from two phase III trials of the tyrosine kinase inhibitor gefitinib in NSCLC have been of concern to some. However, many factors may have contributed to this outcome, and it is not necessarily predictive of the future usefulness of these agents. Patient characteristics, lack of patient selection, dosing schedule, and trial design may all have played roles. It is important to remember that intracellular targeting of HER is a relatively novel approach, and our knowledge of how best to optimize such treatment is still unfolding. More clinical experience is needed.