Tissue transglutaminase is a multifunctional protein that is likely to play a role in numerous processes in the nervous system. Tissue transglutaminase posttranslationally modifies proteins by transamidation of specific polypeptide bound glutamines. This action results in the formation of protein crosslinks or the incorporation of polyamines into substrate proteins, modifications that likely have significant effects on neural function. Tissue transglutaminase is a unique member of the transglutaminase family as in addition to catalyzing the calcium-dependent transamidation reaction, it also binds and hydrolyzes ATP and Guanosine 5'-triphosphate and may play a role in signal transduction. Tissue transglutaminase is a highly regulated and inducible enzyme that is developmentally regulated in the nervous system. In vitro, numerous substrates of tissue transglutaminase have been identified, and several of these proteins have been shown to be in situ substrates as well. Several specific roles for tissue transglutaminase have been described and there is evidence that tissue transglutaminase may also play a role in apoptosis. Recent findings have provided evidence that dysregulation of tissue transglutaminase may contribute to the pathology of several neurodegenerative conditions including Alzheimer's disease and Huntington's disease. In both of these diseases tissue transglutaminase and transglutaminase activity are elevated compared to age-matched controls. Further, immunohistochemical studies have demonstrated that there is an increase in tissue transglutaminase reactivity in affected neurons in both Alzheimer's and Huntington's disease. Although intriguing, many issues remain to be addressed to definitively establish a role for tissue transglutaminase in these neurodegenerative diseases.