Drug delivery across cellular barriers, such as intestinal, nasal, buccal, alveolar, vaginal, ocular and blood-brain, is a challenging task. Multiple physiological mechanisms, such as cellular organisation, efflux, and chemical and enzymatic degradation, as well as physicochemical properties of the drug molecule itself, determine the penetration of xenobiotics across epithelial cell layers. Limited intestinal absorption of many novel and highly potent lead compounds has stimulated an intense search for strategies that can effectively enhance permeation across these biological barriers. This review discusses some of the approaches that have been, and are currently being, investigated for transepithelial drug delivery. Transdermal drug delivery requires a separate discussion on its own and is thus outside the scope of this review article.