This article reviews key advances in ion-selective electrode technology that have made potentiometric measurements of ionized calcium (Ca2+) reliable and precise. Our use of two second-generation Ca2+ analyzers (Radiometer ICA1 and NOVA 8) made possible uninterrupted service as volume increased to 31 640 patient tests in 1985. The lower results on the NOVA 8 were adjusted upwards to match those of the ICA1 to give identical results. Both analyzers were evaluated under working conditions of high volumes and multiple operators to establish downtime, electrode life, and costs. We have classified all Ca2+ analyzers into first-, intermediate-, and second-generation instruments, the better to understand their differences. Results for large numbers of patients' sera were shown to be systematically different when any two analyzers were compared. These differences are the consequence of each manufacturer's unique choices of the following: (a) the matrix of the calcium calibration solutions, (b) the type and configuration of the reference electrode, and (c) the salt-bridge solution. Elimination of each analyzer's biases will require agreement on a reference system that defines the accuracy of Ca2+ measurements on serum, plasma, or whole blood. The sound analytical performance of today's second-generation Ca2+ analyzers has allowed us to exploit the inherent superiority of Ca2+ over total calcium (CaT) measurements in the daily care of patients. We report on the preference of Ca2+ over CaT by physicians at our hospital since the introduction of second-generation Ca2+ analyzers. Therefore, we state unequivocally from our very satisfactory experience over the past five years that Ca2+ is a clinical laboratory test whose time has come!