As the indispensable second cellular messenger, calcium signaling is involved in the regulation of almost all physiological processes by activating specific target proteins. The importance of calcium ions (Ca 2+) makes its “Janus nature” strictly regulated by its concentration. Abnormal regulation of calcium signals may cause some diseases; however, artificial regulation of calcium homeostasis in local lesions may also play a therapeutic role. “Calcium overload,” for example, is characterized by excessive enrichment of intracellular Ca 2+, which irreversibly switches calcium signaling from “positive regulation” to “reverse destruction,” leading to cell death. However, this undesirable death could be defined as “calcicoptosis” to offer a novel approach for cancer treatment. Indeed, Ca 2+ is involved in various cancer diagnostic and therapeutic events, including calcium overload-induced calcium homeostasis disorder, calcium channels dysregulation, mitochondrial dysfunction, calcium-associated immunoregulation, cell/vascular/tumor calcification, and calcification-mediated CT imaging. In parallel, the development of multifunctional calcium-based nanomaterials ( e.g., calcium phosphate, calcium carbonate, calcium peroxide, and hydroxyapatite) is becoming abundantly available. This review will highlight the latest insights of the calcium-based nanomaterials, explain their application, and provide novel perspective. Identifying and characterizing new patterns of calcium-dependent signaling and exploiting the disease element linkage offer additional translational opportunities for cancer theranostics.