In this chapter, the attention is put on Ca2+ effect on Clusterin (CLU) activity. We showed that two CLU forms (secreted and nuclear) are differently regulated by Ca2+ and that Ca2+ fluxes affect CLU gene expression. A secretory form (sCLU) protects cell viability whereas nuclear form (nCLU) is proapoptotic. Based on available data we suggest, that different CLU forms play opposite roles, depending on intracellular Ca2+ concentration, time-course of Ca2+ current, intracellular Ca2+ compartmentalization, and final Ca2+ targets. Discussion will be motivated on how CLU acts on cell in response to Ca2+ waves. The impact of Ca2+ on CLU gene activity and transcription, posttranscriptional modifications, translation of CLU mRNA, and posttranslational changes as well as biological effects of CLU will be discussed. We will also examine how Ca2+ signal and Ca2+-dependent proteins are attributable to changes in CLU characteristics. Some elucidation of CLU gene activity, CLU protein formation, maturation, secretion, and intracellular translocations in response to Ca2+ is presented. In response to cell stress (i.e., DNA damage) CLU gene is activated. We assume that commonly upregulated mRNA for nCLU versus sCLU and vice versa are dependent on Ca2+ accessibility and its intracellular distribution. It looks as if at low intracellular Ca2+ the delay in cell cycle allows more time for DNA repair; otherwise, cells undergo nCLU-dependent apoptosis. If cells are about to survive, intrinsic apoptosis is abrogated by sCLU interacting with activated Bax. In conclusion, a narrow range of intracellular Ca2+ concentrations is responsible for the decision whether nCLU is mobilized (apoptosis) or sCLU is appointed to improve survival. Since the discovery of CLU, a huge research progress has been done. Nonetheless we feel that much work is left ahead before remaining uncertainties related to Ca2+ signal and the respective roles of CLU proteins are unraveled.