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Ca²⁺ is one of the key regulators of cell survival, but Ca²⁺ can also induce apoptosis in response to a variety of pathological conditions. The pro-apoptotic effects of Ca²⁺ are mediated by a diverse range of Ca²⁺-sensitive factors that are compartmentalized in various intracellular organelles including the ER, cytoplasm, and mitochondria. The Ca²⁺ dynamics of these organelles appear to be modulated by the apoptosis-regulating Bcl-2 family proteins. In this paper, the recent progress of research on the mechanisms mediating the apoptosis-regulating effects of Ca²⁺ and the interactions of Bcl-2 family proteins with the Ca²⁺ storage organelles are discussed.