Despite the importance of Zn(II) in the regulation of metalloenzymes and transcription factors, very little is known about the involvement of intracellular fluxes of Zn(II) in the regulation of cellular events. A major role for Zn(II) may be as a negative regulator of the cellular suicide process of apoptosis since deprivation of Zn(II), in vitro or in vivo, enhances the rate of apoptosis while Zn(II) supplementation lowers it. Apoptosis is a gene-directed active mechanism of cell death required for organ/tissue development and with important implications for a number of diseases including cancer, AIDS, diabetes and neurodegenerative disorders associated with aging. To further understanding of the role of Zn(II) in the regulation of apoptosis, we have used a sulphonamidoquinoline-based Zn(II)-specific fluorophore Zinquin to monitor the more labile Zn(II) pools in various types of cell and to correlate fluxes of Zn(II), triggered pharmacologically or by physiological stimuli, with susceptibility of cells to undergo apoptosis. In parallel biochemical studies, we have addressed the question of what is the critical target(s) of Zn(II) in the molecular cascade of events leading to cell death. Three observations will be discussed. First, relatively small changes in Zinquin-detectable intracellular Zn(II) led to profound changes in susceptibility of various types of cells to apoptose. In particular, Zn(II)-chelating agents synergized with cytotoxic drugs in killing cancer cells and may therefore have an adjuvant role in anti-cancer therapy. Despite this finding, a major reduction in Zinquin-detectable Zn(II) in pancreatic islet cells during development of type II diabetes did not predispose these cells to apoptosis, suggesting that the major pool of Zn(II) detected by Zinquin in islet cells is unlikely to be involved in suppression of apoptosis. This pool of Zn(II) was largely intragranular and probably represents Zn(II) complexed with insulin. Secondly, during the process of apoptosis, there was a substantial, focal release of Zn(II) into the cytoplasm, as detected by intense staining with Zinquin. We speculate that this release is due to the mobilization of tightly-bound pools of Zn(II) which now become available for binding to Zinquin. The possible role of oxidative stress in this Zn(II) release will be discussed. Finally, we have identified at least two steps in the apoptotic cascade which are suppressed by Zn(II). One of these steps occurs during the activation of a critical death-inducing cytosolic protease named caspase-3, and may involve the suppression by Zn(II) of a protease required for caspase-3 processing. The second step, downstream of caspase-3 activation, involves suppression of endonuclease-mediated cleavage of DNA, a common event in apoptosis that is usually triggered by a calcium ion flux. These studies provide a basis for understanding the mechanism of the widespread cell death that occurs in many organs and tissues during primary zinc deficiency or in disorders associated with abnormalities in Zn(II) homeostasis and metabolism.