Calcium ions (Ca) and the complex regulatory system governed by Ca signaling have been described to be of crucial importance in numerous aspects related to cell life and death decisions, especially in recent years. The growing attention given to this second messenger is justified by the pleiotropic nature of Ca-binding proteins and transporters and their consequent involvement in cell fate decisions. A growing number of works highlight that deregulation of Ca signaling and homoeostasis is often deleterious and drives pathological conditions; in particular, a disruption of the main Ca-mediated death mechanisms may lead to uncontrolled cell growth that results in cancer. In this work, we review the latest useful evidence to better understand the complex network of pathways by which Ca regulates cell life and death decisions.