Transglutaminase 2 (TG2; ) is the most abundantly expressed member of the transglutaminase family and exerts opposing effects on cell growth, differentiation and apoptosis via multiple activities, including transamidase, GTPase, cell adhesion, protein disulfide isomerase, kinase and scaffold activities. It is distributed in and around various parts of a cell, including the extracellular matrix, plasma membrane, cytosol, mitochondria and nucleus. Generally, nuclear TG2 represents only 5–7% of the total TG2 in a cell, and various stimuli will increase nuclear TG2 via cellular stress and/or an increased intracellular Ca2+ concentration. There is increasing evidence indicating the importance of nuclear TG2 in regulating gene expression via post–translational modification of (or interaction with) transcriptional factors and related proteins. These include E2F1, hypoxia inducible factor 1, Sp1 and histones. Through this mechanism, TG2 controls cell growth or survival, differentiation and apoptosis, and is involved in the pathogenesis and/or treatment of neurodegenerative diseases, liver diseases and cancers. The balance between import from the cytoplasm to the nucleus, and export from the nucleus to the cytoplasm, determines the level of TG2 in the nucleus. Selective regulation of the expression, activity or localization of nuclear TG2 will be important for basic research, as well as clinical applications, suggesting a new era for this long–studied enzyme.