Expression of epidermal growth factor and its transmembrane receptor (EGFR) stimulates tumor growth. Matuzumab is a humanized anti-EGFR monoclonal antibody that blocks EGFR activation and downstream signaling, inhibits tumor growth, and provides a clinical benefit for some patients. The plasma half-life (6-10 days) and pharmacodynamic activity allow flexible dosing on weekly, every-2-week, and every-3-week schedules. Matuzumab has shown single-agent antitumor activity in heavily pretreated patients with a variety of tumors, with a favorable safety profile. Skin rash is the most common toxicity, but is severe (Grade 3) in < 1 percent. This article describes preclinical and clinical development of matuzumab.