Hosts and microbes have co-evolved over millions of years. Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated diseases. Although the etiology of IBD remains an enigma, various studies have proposed the involvement of mucosa-associated Escherichia coli (E. coli) strains in the pathogenesis of IBD. E. coli, a usual inhabitant of the intestine, causes disease after acquiring virulence factors; however, the mechanisms underlying this phenomenon are not well understood. In the present review, we will discuss recent findings on how gut E. coli regulates and controls gut homeostasis and the pathogenesis of IBD. We will also summarize current knowledge regarding the cause, mechanism, genetics, and environmental factors involved in the regulation of IBD. Furthermore, we will discuss the possibility of alterations in innate and acquired immunity during the course of disease as well as possible treatment.