Colorectal cancer (CRC) has a multifactorial etiology. Although the exact cause of CRC is still elusive, recent studies have indicated microbial involvement in its etiology. Escherichia coli has emerged as an important factor in CRC development since the bacterium can cause changes in the gut that lead to cancerous transformation. A number of studies indicate that chronic inflammation induced by microorganisms, including E. coli, during inflammatory bowel disease (IBD) predisposes an individual to CRC. The evidence that support the role of E. coli in the etiology of CRC, through IBD, is not limited only to chronic inflammation. The growth of E. coli as an intracellular pathogen during IBD and CRC enable the bacteria to modulate the host cell cycle, induce DNA damage and accumulate mutations. These are some of the contributing factors behind the etiology of CRC. The present article considers the current status of the involvement of E. coli, through IBD, in the etiology of CRC. We discuss how intracellular E. coli infection can cause changes in the gut that can eventually lead to cellular transformation. In addition, the recent management strategies that target E. coli for prevention of CRC are also discussed.