Calcium ions in plasma are either free (ionized calcium) or bound to protein and small anions. Ionized calcium is the physiologically active fraction. Several factors have recently been combined to change the measurement of ionized calcium from a specialized to a routine test. Reliable instrumentation, easy to maintain, is now available with simultaneous pH measurement. This paper focuses on both the analytical consideration required to perform reliable laboratory measurements and the clinical situations where ionized calcium has proved to provide a substantially different clinical interpretation than the measurement of total calcium.