Apoptotic cells show morphological modifications which occur as the result of complex molecular mechanisms involving several proteins including 'tissue' transglutaminase (tTG). Although tTG was originally thought to be responsible for the protein crosslinks which prevent the leakage of intracellular components, thereby reducing inflammation and autoimmunity, recent evidence indicates that tTG is a multifunctional enzyme involved in the complex upstream regulation of the apoptotic machinery: (i) it functions as a GTP-binding protein to transduce signals; (ii) it binds/crosslinks only specific cytosolic and nuclear substrates, suggesting highly specific actions, e.g. on intermediate filaments and in cell cycle control; (iii) it is finely tuned by Ca2+, GTP, S-nitrosylation, polyamines. In light of these recent discoveries, the role of tTG in the regulation of the crucial balance between survival and death is clearly complex.