Purpose of Review <p>Calcification, the deposition of phosphate-calcium crystals, is essential for the development and function of mineralized tissues. When dysregulated, it can cause harmful effects. This review focuses on the critical role of the balance between phosphate (Pi) and pyrophosphate (PPi) in maintaining healthy mineralization and explains how disruptions in this balance contribute to rare calcifying disorders.</p> Recent Findings <p>Studies have identified key regulators of PPi production and Pi generation. Recent research on rare calcifying diseases and animal models has revealed how Pi/PPi imbalances lead to ectopic calcification in soft tissues, driving disease progression.</p> Summary <p>The balance of Pi/PPi is vital for bone health and preventing pathological calcification. Disruptions in this equilibrium contribute to rare diseases. Understanding these mechanisms, supported by preclinical models, opens potential therapeutic avenues to restore balance and mitigate the impact of these diseases.</p>