Cell death programmes are generally defined by biochemical/genetic routines that are linked to their execution and by the appearance of more or less typical morphological features. However, in pathological settings death signals may engage complex and interacting lethal pathways, some of which are common to different cells, whereas others are linked to a specific tissue and differentiation pattern. In neurons, death programmes can be spatially and temporally segregated. Most importantly physiological Ca2+ signals are essential for cell function and survival. On the other hand, Ca2+ overload or perturbations of intracellular Ca2+ compartmentalization can activate or enhance mechanisms leading to cell death. An imbalance between Ca2+ influx and efflux from cells is the initial signal leading to Ca2+ overload and death of ischaemic neurons or cardiomyocytes. Alterations of intracellular Ca2+ storage can integrate with death signals that do not initially require Ca2+, to promote processing of cellular components and death by apoptosis or necrosis. Finally, Ca2+ can directly activate catabolic enzymes such as proteases, phospholipases and nucleases that directly cause cell demise and tissue damage.