Our bodies are protected from the external environment by mucosal barriers that are lined by epithelial cells. The epithelium plays a critical role as a highly dynamic, selective semipermeable barrier that separates luminal contents and pathogens from the rest of the body as well as controlling the absorption of nutrients, fluid and solutes (1, 2). A series of protein complexes including the adherens junction, desmosomes, and tight junctions (TJ) function as the principal barrier in paracellular diffusion (3) as well as regulators of intracellular solute, protein and lipid transport (4). TJs are composed of a series of proteins called occludins, junctional adhesion molecules (JAM), and claudins (5, 6) that reside primarily as the most apical intercellular junction. Here we will review one of these protein families, claudins, and their relevance to gastrointestinal and liver diseases.