Escherichia coli is one of the most well-studied bacterial species, but several significant knowledge gaps remain regarding its ecology and natural history. Specifically, the most important factors influencing its life as a member of the healthy human gut microbiome are either underevaluated or currently unknown. Distinct E. coli population dynamics have been observed over the past century from a handful of temporal studies conducted in healthy human adults. Early studies using serology up to the most recent studies using genotyping and DNA sequencing approaches have all identified long-lived E. coli residents and short-lived transients. This review summarizes these discoveries and other studies that focused on the underlying mechanisms that lead to establishment and maintenance of E. coli residency in healthy human adults. Many fundamental knowledge gaps remain and are highlighted with the hope of facilitating future studies in this exciting research area.