Calcium-based approaches have not shifted the course of many chronic diseases because the dominant defect is disordered Calcium handling, with compartment mislocalization and pathological trapping rather than a simple deficiency. This session positions calcium as a central regulatory axis in chronic disease, linking impaired Calcium signal transduction and compartmental control to sustained inflammatory tone, dysregulated excitability, and loss of coordinated cellular function, and explaining how restoring controlled Calcium handling can shift disease behavior across conditions. We introduce AIC Therapy as an upstream correction strategy to restore calcium signaling and reduce pathological calcium deposition, with direct implications for clinical application.