Although longstanding experimental evidence has associated alterations of calcium homeostasis to cell death, only in the past few years the role of calcium in the signaling of apoptosis has been extensively investigated. In this review, we will summarize the current knowledge, focusing on (i) the effect of the proteins of the Bcl-2 family on ER Ca 2+ levels,(ii) the action of the proteolytic enzymes of apoptosis on the Ca 2+ signaling machinery,(iii) the ensuing alterations on the signaling patterns of extracellular stimuli, and (iv) the intracellular targets of ‘apoptotic’Ca 2+ signals, with special emphasis on the mitochondria and cytosolic Ca 2+-dependent enzymes.