Clinical and neonatal screening methods using a tandem mass spectrometer are clearly a model for modern laboratory testing in the new Millennium. By the year 2000, more than 1 million blood and plasma samples will have been tested in laboratories throughout the world for a battery of metabolic disorders using a tandem mass spectrometer as the primary analytical device. A tandem mass spectrometer is considered the "ultimate" analytical detector in a variety of biochemical and clinical methods because of its very high accuracy, selectivity, precision, versatility and robust nature. The ability to achieve very high and reproducible sample throughput (approximately 600 samples/instrument/24 h) has made this technology cost-effective for newborn screening. In order to reliably measure markers of inborn errors of metabolism while maintaining low costs and high efficiency, accuracy and quality, much attention needs to be placed on monitoring and maintenance of all components of the entire testing system. These components include specimen collection and sample preparation methods, analysis by LC tandem mass spectrometry, conversion of raw mass spectra (data) into clinically meaningful results (concentration), expert interpretation of these results so that the clinician can be provided with information to facilitate a diagnose, and follow-up and education so that the maximum benefits of newborn screening translate into prevention of disease symptoms or more effective treatments. Addressing each part of the whole system will produce a quality screening program that will detect a battery of disorders using tandem mass spectrometry with a disease frequency of nearly 1 in 4000 infants.