Convincing evidence demonstrates that ionized calcium and not total calcium is the physiologically relevant component of blood calcium. Direct measurement of ionized calcium, however, is limited by difficulties in accurate analysis, lack of standardization, and need for special handling, all resulting in increased cost; therefore, strategies have been developed to estimate ionized calcium from total calcium adjusted for levels of albumin, measurements that are more available and relatively inexpensive. This commentary compares the advantages and limitations of direct or calculated determinations of ionized calcium. Also examined are available data illustrating the settings in which measurement of ionized calcium is preferred and, in some cases, necessary for clinical decision-making.