The role of calcium in cell injury has been the subject of much recent investigation. The movement and redistribution of this cation from extra to intracellular compartments and the calcium shifts between intracellular compartments may well play a determinate role in the cell's reaction to injury. Therefore, data of such shifts and their correlation with morphological, biochemical and cytoskeletal studies will provide a better understanding of these processes. To study the effects of calcium regulation on acute lethal anoxic injury and the effects of inhibition of respiration with cyanide, three experimental systems were utilized: Ehrlich ascites tumor cells, isolated rabbit proximal tubule segments and suspended or cultured rat proximal tubule cells. Although our data showed no correlation between total cell calcium and cell death except in highly selected cell systems, they did indicate that calcium can be an important control variable. Therefore, massive increases in total cell calcium, as seen in Ca3(PO4)2 precipitation in mitochondria, must be a secondary event and represent the modern day equivalent of the classical dystrophic calcification seen by pathologists in the past. Although the involvement of extracellular calcium in cell death may well be significant in some cell types, redistribution of calcium within the intracellular compartments may play an even more important role.