Transglutaminase2 is a pleiotropic enzyme expressed ubiquitously and abundantly. It has been implicated in a variety of physiological processes, such as growth, differentiation, migration, signaling, cytoprotection, cell death and survival, wound healing, angiogenesis, inflammation, apoptosis and autophagy. It operates intra cellularly in multiple organelles, extracellularly and on cell surface. Apart from catalyzing post-translational modifications of proteins, by deamidation and cross-linking, it exercises G-protein, isomerase and kinase activities and non-enzymatic biological functions. Aberrant activation or deregulation of its functions is involved in numerous human disease. The most known one is celiac disease, but the present review will expand on extraintestinal entities. It plays a role in inflammatory, degenerative-age related, neurodegenerative, malignant, metabolic and hormonal, autoimmune and genetic conditions. Increased knowledge of its structure, functions and regulation in homeostatic phase, open the opportunity to design new therapeutic strategies to inhibit its malfunction in pathological situations.