Enteropathogenic Escherichia coli (EPEC) primarily cause gastrointestinal illness in neonates. They accomplish this by a complex coordinated multistage strategy, whereby the organisms colonize the epithelial lining of the small intestine. This process can be divided into four stages: first, localized, nonintimate adherence; second, type III secretion-mediated injection of effector proteins, third effacement of microvilli and, finally, intimate adherence. In this article, we review the history and current state of knowledge, as well as present potential future directions for further investigating the fascinating processes by which EPEC and related organisms colonize the human intestine and cause disease.