Newborn screening (NBS) represents the largest volume of genetic testing. The 45-year history of NBS has demonstrated its benefits, as well as the importance of an evidence base. The recent addition of tandem mass spectrometry (MS/MS) resulted in a fivefold increase in the number of tests. Experience with MS/MS also showed that laboratory tests are just one part of the NBS system. The lessons learned from NBS will provide important insights as we move into the predictive, preventive, and personalized era of genomic medicine.