The concept of neonatal screening for metabolic disorders was launched by Robert Guthrie in 1963. A filter paper blood sample and a cheap and rapid analytical technique were factors that paved the road to success. Mass screening for phenylketonuria soon started to spread. Various additional screening procedures for other metabolic or endocrine conditions were subsequently developed. Most of developed countries have set up systematic neonatal screening programs and million of babies are screened each year. This review presents the main milestones of the fantastic history of neonatal screening but also the questions risen by many temptations to extend the screening to other disorders which not necessarily fulfil classic criteria for systematic search. Ethical and health economical aspects will be the most important issues for the development of neonatal screening in the next millennium.