The formation of insoluble protein deposits is a common hallmark of most neurodegenerative diseases. The disease-specific lesions arise from pathogenic modifications of proteins or defects of their breakdown. Transglutaminases posttranslationally modify proteins by transamidation of specific protein-bound glutamines to specific protein-bound lysines. This action results in the formation of covalent crosslinks between proteins, a modification likely to have profound effects on nerve cell function. Crosslinking of proteins via Nϵ(γ-glutamyl)lysine bonds by transglutaminases has been described in in vitro and animal models of neuron loss. Recent findings provided evidence that dysregulation of transglutaminase activity may contribute to the pathology of various neurodegenerative diseases, including polyglutamine expansion diseases and primary neurodegenerative dementias, the prototype of which is Alzheimer's disease (AD). Transglutaminase activity and expression was shown to be elevated in AD and Huntington's disease (HD) compared to age-matched controls by several studies. Further, crosslinks have been found to colocalize with neurofibrillary tangles characteristic of Alzheimer's pathology by immunocytochemistry. Recent data showed increased crosslink concentrations in the cerebrospinal fluid of HD patients. A series of studies from our laboratory showed that elevated crosslink concentrations in cerebrospinal fluid are characteristic of AD as well as other related dementias associated with the formation of intraneural inclusions. Although many issues remain to be addressed to establish a definitive model for the formation of specific histopathological lesions, crosslinking proteins by transglutaminases offers a plausible explanation for the stabilization of noxious protein aggregates and may reveal a common pathogenic mechanism in various primary neurodegenerative diseases. Drug Dev. Res. 56:458–472, 2002. © 2002 Wiley-Liss, Inc.