A variety of chemical compounds are currently being discussed as novel drug delivery strategies. One promising strategy is to selectively open the paracellular pathway of epithelia for the passage of macromolecules. A prerequisite for this effect is a rapid and reversible action of these compounds, to allow a marked translocation of a drug, but also to avoid unwanted adverse effects, such as the translocation of noxious agents. Bioactive molecules that elevate paracellular permeability include Ca2+ chelators, bacterial toxins, and other compounds, some of which perturb the structural basis of epithelial barrier function—the tight junction. Within the tight junction, organ- and tissue-specific barrier properties are determined mainly by claudins. The majority of members of the claudin protein family seal the paracellular pathway. This paper focuses on recent approaches concerning absorption-enhancing effects, with regard to selectivity and mechanism.