Transglutaminases (TG, E.C. 22.214.171.124) are a family of related and ubiquitous enzymes which catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. These enzymes are also capable of catalyzing other reactions which are important for cell life. The distribution and the physiological roles of human TGs have been widely studied in numerous cell types and tissues and recently their roles in several diseases have begun to be identified. It has been hypothesized that transglutaminase activity is directly involved in the pathogenetic mechanisms responsible for several human diseases. In particular, “tissue” TG (tTG, type 2), a member of the TG enzyme family, has been recently shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD), which is characterized, in part, by aberrant transglutaminase activity and by the presence of transglutaminase-modified proteins. In this review we describe the biochemistry of TGs, with particular reference to the molecular mechanisms involved in the physiopathology of this human disease, as a model for the study of other immunological disorders.