Coeliac disease is a multifactorial disease characterized by a dysregulated 
immune response to ingested wheat gluten and related cereal proteins. With an 
incidence of about 1% of the general population, it is considered the most 
common food intolerance disorder. The mainstay of coeliac disease treatment is 
strict lifelong adherence to a gluten-free diet. Elimination of gluten and 
related proteins from the diet leads to clinical and histological improvement. 
However, some patients do not respond to dietary therapy and others have poor 
dietary compliance. This has prompted the search for a therapy alternative to a 
gluten-free diet. Tissue transglutaminase is a crucial factor in coeliac disease 
because it promotes the gluten-specific T-cell response and is also the target 
of the autoimmune response. Tissue transglutaminase induces changes in gluten, 
which in turn, cause the generation of a series of gluten peptides that bind to 
HLA-DQ2 or DQ8 molecules with high affinity. The resulting HLA-DQ2 (DQ8)-gluten 
peptide interaction triggers the proinflammatory T cell response. Tissue 
transglutaminase is also involved in other non-T-cell-mediated biological 
activities of gliadin peptides. For these reasons, tissue transglutaminase is a 
potential target for therapeutic intervention. In this paper we review the 
state-of-the-art of tissue transglutaminase inhibition, and examine known and 
new-generation inhibitors and their activity in in vitro and in vivo models. We 
also examine their potential as therapeutic tools for coeliac disease.