The traditional focus of newborn screening for inherited metabolic diseases is to test infants for medical conditions that may cause significant morbidity and mortality unless treatment is initiated early. A major change began with the application of tandem mass spectrometry to the quantitative analysis of amino acids and acylcarnitines in dried blood spots. Beyond the lack of a consensus on disease selection, the pace of introduction for expanded screening programs has been slow and patchy among and within countries. Universal metabolic screening poses important ethical issues, related to possible ambiguous findings, late-onset diseases, conditions, such as lysosomal storage disorders, with no clear-cut evidence on when and how to start a therapy. The possible application of next generation sequencing to newborn screening has been recently proposed. In the near future it will be also possible to perform a genetic and mutational scan across the whole genome of the fetus in a non-invasive manner by analyzing cell-free fetal DNA in maternal blood as early as the 5th week of gestational age. These high-throughput methods applied to neonatal and non-invasive prenatal screening of genetic diseases, including inborn errors of metabolism, are raising further technical, political and ethical issues.