The relationship between transglutaminase activity, apoptosis and the propensity of a tumour to metastasise, was investigated in a series of metastatic variants of an HSV-2 induced hamster fibrosarcoma and two metastatic variants of the B16 mouse melanoma. The data suggest an inverse relationship between metastatic potential and cytosolic transglutaminase activity. A direct relationship was found between measured cytosolic activity and the levels of the endogenous product of transglutaminase, the protein crosslink epsilon(gamma-glutamyl)lysine. Increasing metastatic potential and decreasing cytosolic transglutaminase activity was accompanied by a corresponding decrease in the number of detergent-insoluble apoptotic envelopes isolated from variant cell lines. These apoptotic envelopes were found to be highly crosslinked structures, containing more than 85% of the cells content of epsilon(gamma-glutamyl)lysine. These data are in keeping with the idea that a major role for the cytosolic transglutaminase is in the formation of the highly crosslinked apoptotic envelope during programmed cell death and that perturbation of this function may be an important determinant in the development of the metastatic phenotype.