In this paper we discuss the role of "tissue" transglutaminase (tTG) in apoptosis. This enzyme by catalizing the Ca(2+)-dependent cross-linking of intracellular proteins leads to the formation of the SDS-insoluble protein scaffold in cells undergoing programmed cell death. These intracellular structures confer resistance to mechanical and chemical attack to the polipeptides involved in the linkages. tTG is induced during apoptosis, in fact, tTG mRNA is transcripted as a consequence of apoptosis induction. Overexpression of tTG in many cell lines enhances their susceptibility to apoptosis, indicating a pivotal role for tTG in this process. In keeping with these findings transfection of the human tTG complementary DNA in antisense orientation leads in a pronounced decrease of both spontaneous as well as induced apoptosis. Interestingly, the identification of the tTG substrate proteins in cells undergoing apoptosis has evidenced that many of the tTG proteins are also substrates of caspases.