In 1888, Pierre Ménétrier first described the disease that bears his name. Many of the findings he reported then remain accepted features of the disease. Based on studies performed in our laboratory over the past 20 years, we have implicated increased transforming growth factor-α (TGFα) expression and heightened epidermal growth factor receptor (EGFR) activity in the pathogenesis of Ménétrier's disease. Herein, we provide a historical perspective of this rare disorder, review our experience with Ménétrier's disease, and discuss future challenges and opportunities posed by this disorder.