The intestinal epithelium performs a multitude of tasks related to digestion and homeostasis. As a consequence of ingestion, this tissue must also participate in activities associated with protecting the body from potential pathogenic agents and toxic materials. To efficiently perform tasks associated with digestion and these protective functions, the intestinal epithelium has established several anatomical, biochemical and physiological barriers to impede unregulated uptake of materials. In order to perform functions of digestion and homeostasis, the intestinal epithelium uses mechanisms that allow dynamic modulation of regulated uptake pathways that can respond rapidly to changes in diet, health and challenges from pathogenic agents and macromolecules. This review focuses on specific, recent advances made in understanding cellular pathways and mechanisms that regulate dynamic processes of these barriers and examines the feasibility of drug delivery strategies focusing on macromolecular therapeutics potentially useful in the treatment of inflammatory bowel disease (IBD).