Ca²⁺ is a universal messenger regulating many physiological functions including such an important one, as the ability of the cell to undergo orderly self-destruction upon completion of its mission, called apoptosis. If this function is compromised unwanted cells may eventually take over the tissue turning it into a cancer. Ca²⁺ dependency of apoptosis, when its all aspects are learned and understood and key molecular players identified, may provide a good opportunity for controlling tumor growth. In the present mini-review we describe the major molecular determinants of Ca²⁺ homeostasis in prostate cancer cells and establish their role in the transformation to apoptosis-resistant cell phenotypes typical of advanced androgen-independent prostate cancer. We show that the hallmark of such transformation is the inhibition of apoptosis pathway associated with endoplasmic reticulum Ca²⁺ store depletion.