Physiological stimuli causing an increase of cytosolic free Ca2+ [Ca2+], or the release of Ca2+ from the endoplasmic reticulum invariably induce mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free [Ca2+] ([Ca2+]m). The [Ca2+]m rise occurs despite the low affinity of the mitochondrial Ca2+ uptake systems measured in vitro and the often limited amplitude of the cytoplasmic [Ca2+]c increases. The [Ca2+]m increase is typically in the 0.2-3 microM range, which allows the activation of Ca2(+)-regulated enzymes of the Krebs cycle; and it rapidly returns to the resting level if the [Ca2+], rise recedes due to activation of mitochondrial efflux mechanisms and matrix Ca2+ buffering. Mitochondria thus accumulate Ca2+ and efficiently control the spatial and temporal shape of cellular Ca2+ signals, yet this situation exposes them to the hazards of Ca2+ overload. Indeed, mitochondrial Ca2+, which is so important for metabolic regulation, can become a death factor by inducing opening of the permeability transition pore (PTP), a high conductance inner membrane channel. Persistent PTP opening is followed by depolarization with Ca2+ release, cessation of oxidative phosphorylation, matrix swelling with inner'membrane remodeling and eventually outer membrane rupture with release of cytochrome c and other apoptogenic proteins. Understanding the mechanisms through which the Ca2+ signal can be shifted from a physiological signal into a pathological effector is an unresolved problem of modern pathophysiology that holds great promise for disease treatment.