Escherichia coli is one of the most genetically and phenotypically diverse species of bacteria. This remarkable diversity produces a plethora of clinical outcomes following infection and has informed much of what we currently know about host-pathogen interactions for a wide range of bacteria-host relationships. In studying the role of microbes in disease, adherent-invasive E. coli (AIEC) has emerged as having a strong association with Crohn's disease (CD). Thus, there has been an equally strong effort to uncover the root origins of AIEC, to appreciate how AIEC differs from other well-known pathogenic E. coli variants, and to understand its connection to disease. Emerging from a growing body of research on AIEC is the understanding that AIEC itself is remarkably diverse, both in phylogenetic origins, genetic makeup, and behavior in the host setting. Here, we describe the unique lifestyle of CD-associated AIEC and review recent research that is uncovering the inextricable link between AIEC and its host in the context of CD.