Apoptosis is a process of major biomedical interest, since its deregulation is involved in the pathogenesis of a broad variety of disorders (neoplasia, autoimmune disorders, viral and neurodegenerative diseases, to name a few). It is now firmly established that variations in cellular calcium (Ca2+) concentration are pivotal in the control of a variety of cellular functions. Strong evidence has been accumulated supporting a central role of Ca2+ in the regulation of cell death. In particular, in the context of the biochemical mechanisms of apoptosis, increasing evidence support a role for endoplasmic reticulum (ER)-mitochondria Ca2+ cross talk as a crucial regulator of several pathways of apoptosis. Recent data highlight as also the promyelocytic leukemia protein (PML), by modulating the ER machinery at the contact sites between ER and mitochondria (the mitochondria associated membranes, MAMs), regulates cell survival through the ER-cytosol/mitochondria Ca2+ signaling.