Gluten is one of the most ubiquitous ingredients in the human diet. The unique physicochemical properties of this biomaterial are the result of its primary structure (rich in Pro and Gln residues), secondary structure (abundance of non-hydrogen bond dependent polyproline II helices), and tertiary and quarternary structures (extensive intra- and intermolecular disulfide linkages). From a biological perspective, although the nutritional characteristics of gluten are well understood, its toxicological effects in certain individuals are only just beginning to be appreciated. Celiac Sprue, a widespread disease, is perhaps the best dissected form of gluten intolerance, where dietary gluten elicits an elaborate immune response that leads to enteropathy in the upper small intestine and a wide range of gastrointestinal as well as extraintestinal symptoms. A growing body of evidence suggests that a combination of proteolytic resistance and high affinity for two human proteins - transglutaminase 2 and HLA-DQ2 (or alternately HLA-DQ8) - renders pro-inflammatory in the Celiac small intestine. Other forms of gluten sensitivity have also been recognized in the clinic and in animal models of disease, although their precise relationship to gluten structure remains to be elucidated. An enhanced understanding of gluten chemistry and toxicology is spawning the emergence of pharmacological approaches to treat gluten sensitivity, as well as sensitive and accurate methods to quantify gluten content in food products.