The use of mass spectrometry in the care of patients via a clinical laboratory is increasing at a substantial pace. The primary reason is that mass spectrometry, when used appropriately in a clinical laboratory, is an extremely powerful tool for which there are few substitutes in terms of accuracy and precision both analytically and clinically. The reason that this “renaissance” of MS in the clinical lab is occurring now is that these systems are easier to use and do not require a “mass spectrometrist” to operate it. Further, mass spectrometry has attracted much attention in areas of basic science and clinical research which suggests that this technique will be used in a clinical laboratory in the near future. But promise aside, the application of mass spectrometry in the clinical lab has already contributed substantially to the care of our newest generation. In the near term, nearly every infant in the US and many throughout the world will be screened for many treatable metabolic diseases. It has been approximately a 14 years since the concept of using a mass spectrometry to analyze an extract for a few microliters of blood dried on strip of filter paper for hundreds of samples per day was started. There is much to be learned from this application in medicine as an example for further exciting developments. How newborn screening using tandem MS is a model for clinical mass spectrometry will be discussed including lessons learned in its practice.