Crohn’s disease (CD) is characterized by an imbalance of intestinal microbiota and a colonization of subepithelial tissues by pathogen and pathobiont bacteria. Adherent invasive Escherichia coli (AIEC) strains recovered from CD lesions survive and multiply within macrophages. Persistence is one of the mechanisms deployed by AIEC to tolerate macrophages’ attack. The challenging intracellular environment induces a heterogeneity in AIEC LF82 phenotype, including the presence of nongrowing bacteria. This could provide a reservoir for antibiotic-tolerant bacteria responsible for relapsing infections. In this article, we review the conditions leading to AIEC persistence, the relevance of this state for bacterial survival and disease’s etiology, and its implication for therapeutic strategies.