Newborn screening started in the 1960s for the purpose of identifying phenylketonuric patients to begin early intervention and to prevent mental retardation in these patients. Soon thereafter, screening programs expanded to include additional genetic disorders added individually one at a time. In the 1980s, tandem mass spectrometry (MS/MS) was introduced in clinical laboratories, and in the 1990s, the technique was used for newborn screening. Unlike measuring one analyte at a time, MS/MS allows measurement of >40 analytes, in a few minutes with the use of a single assay. Currently, MS/MS is being used for the identification of several amino acid, organic acid and fatty acid disorders. Several states in the United States and many other countries are using MS/MS in newborn screening. However, there is a significant disparity among different newborn screening programs for disorders being screened by MS/MS and many other challenges are faced by the expanded newborn screening. It is anticipated that in the future the use of MS/MS in newborn screening will expand both at the analyte and geographic levels. Clinicians and laboratory scientists should become familiar with MS/MS, disorders being screened in their patients' population and the future of this emerging technology.