Ionized calcium is a physiologically critical calcium pool. It is easily determined, although accuracy depends on sample handling. As a clinical parameter, directly measured ionized calcium has particular import in the care of neonates, patients with sepsis or other cardiovascular instability, massively transfused patients, and those undergoing cardiopulmonary bypass or liver transplantation. Disturbances of calcium occur in many other settings, however, and accurate diagnosis and research conclusions may depend on using the best measurement available. Clinical and investigational use of ionized calcium determinations represent appropriate applications of current proven technology. In the future, clinical calcium manipulation may include modifying specific transmembrane transport processes and intracellular calcium pools and movements. At the current time we are largely restricted to studies of extracellular calcium concentration and its interactions. Much is known, but Mother Nature still has too many secrets. The interested reader is referred to discussions of ionized calcium and hemodynamics, reviews of the endocrine disturbances of calcium and phosphorus, textbook discussions pertinent to general calcium disturbances, and critical care issues.