Oral delivery is the most common and preferred route of drug administration although the digestive tract exhibits several obstacles to drug delivery including motility and intraluminal pH profiles. The gut milieu represents the largest mucosal surface exposed to microorganisms with 10(10-12) colony forming bacteria/g of colonic content. Approximately, one third of fecal dry matter is made of bacteria/ bacterial components. Indeed, the normal gut microbiota is responsible for healthy digestion of dietary fibers (polysaccharides) and fermentation of short chain fatty acids such as acetate and butyrate that provide carbon sources (fuel) for these bacteria. Inflammatory bowel disease (IBD) results in breakage of the mucosal barrier, an altered microbiota and dysregulated gut immunity. Prodrugs that are chemically constructed to target colonic release or are degraded specifically by colonic bacteria, can be useful in the treatment of IBD. This review describes the progress in digestive tract prodrug design and delivery in light of gut metabolic activities.