Calcium (Ca²⁺) is considered one of the most-important biological cations, because it is implicated in cell physiopathology and cell fate through a finely tuned signaling system. In support of this notion, Ca²⁺ is the primary driver of cell proliferation and cell growth; however, it is also intimately linked to cell death. Functional abnormalities or mutations in proteins that mediate Ca²⁺ homeostasis usually lead to a plethora of diseases and pathogenic states, including cancer, heart failure, diabetes, and neurodegenerative disease. In this review, we examine recent discoveries in the highly localized nature of Ca²⁺-dependent signal transduction and its roles in cell fate, inflammasome activation, and synaptic transmission.