Although natural gut microbiota containsEscherichia coli as a commensal, this bacterium, along with other members of the Enterobacteriaceae family, are usually known for their pathogenic potential. Interestingly, E. coli colonizes first and remains all through life, and in fact, some strains possess beneficial properties such as antibacterial colicin secretion. Among the beneficial strains, E. coli Nissle, isolated in 1917, has been the most extensively explored strain. Adaptability to survive under diverse conditions coupled with facile genetic manipulations enabled the design of E. coli strains with properties to deliver antioxidant, anti-inflammatory, and antitumor molecules. Moreover, genetically modified E. coli strains secreting enzymes for converting sucrose and fructose into insulin and mannitol, respectively, were very effective in preventing the onset of metabolic disease by acting as synbiotics. Thus, E. coli is emerging as a very potent probiotic platform for developing strains with the potential of controlling many metabolic and multifactorial diseases, including cancer.