Newborn screening was first introduced as a public health program in the early 1960s. The first disorder detected by modern newborn screening programs was phenylketonuria (PKU). Robert Guthrie developed a simple method using a bacterial inhibition assay that could detect high levels of phenylalanine in blood shortly after a baby was born. Guthrie also pioneered the collection of blood on filter paper which could be easily transported, recognizing the need for a simple system if the screening was going to be done on a large scale. After the success of newborn screening for PKU (39 infants were identified and treated in the first two years of screening, with no false negative results), newborn screening has expanded varying greatly between countries. The role of newborn screening in metabolic diseases and the development of uniform criteria for selection of newborn screening tests will be discussed.