Escherichia coli is likely the most studied organism and was instrumental in developing many fundamental concepts in biology. But why E. coli? In the 1940s, E. coli was well suited for the biochemical and genetic research that blended to become the seminal field of biochemical genetics and led to the realization that processes already known to occur in complex organisms were conserved in bacteria. This now-obvious concept, combined with the advantages offered by its easy cultivation, ultimately drove many researchers to shift from the complexity of eukaryotic models to the simpler bacterial system, which eventually led to the development of molecular biology. As knowledge and experimental tools amassed, a positive-feedback loop fixed the central role of E. coli in research. However, given the vast diversity among bacteria and even among E. coli strains, it was by many fortuitous events that E. coli rose to the top as an experimental model. Here, we share how serendipity and its own biology selected E. coli as the flagship bacterium of molecular biology.