“Tissue” or type 2 Transglutaminase (TG2) is a peculiar multifunctional enzyme able to catalyse Ca2+-dependent posttranslational modification of proteins, by establishing covalent bonds between peptide-bound glutamine residues and either lysine residues or mono- and poly-amines. In addition, it may act also as a G protein in transmembrane signalling, as a kinase, as a protein disulphide isomerase and as a cell surface adhesion mediator. The vast array of biochemical functions exerted by TG2 characterises and distinguishes it from all the other members of the transglutaminase family. Multiple lines of evidence suggest an involvement of the enzyme in neurodegenerative diseases, such as Huntingtons (HD) and Parkinson (PD), and that its inhibition, either via drug treatments or genetic approaches, might be beneficial for the treatment of these syndromes. This review will exploit the recent developments in the comprehension of the role played by type 2 transglutaminase in eukaryotic cells, focusing on the role exerted by TG2 on mitochondrial physiology and on the regulation of cell death pathways at the basis of neurodegenerative diseases.