Each year, millions of infants in the United States and around the world undergo a heel stick for NBS in the first postnatal week. It began in the early 1960s with an NBS program for phenylketonuria (PKU). Dr Robert Guthrie developed both the bacterial inhibition assay (BIA) to detect high concentrations of phenylalanine as well as the filter paper on which blood spots were collected to make high-volume screening possible. NBS expanded slowly throughout the 1970s and 1980s until the application of tandem mass spectrometry, which allows for multiplex testing for many organic acid and fatty acid conditions using one sample. The controversy over whether all of the conditions that can be identified by tandem mass spectrometry should be included in a universal mandatory program was bypassed in 2005 when the Advisory Committee on Heritable Disorders in Newborns and Children endorsed the uniform panel proposed by the American College of Medical Genetics(ACMG) in collaboration with the Health Resources and Services Administration (HRSA). This article reviews several ethical controversies raised by NBS programs, both those already in place (PKU, sickle cell disease, cystic fibrosis) and those under consideration (Duchenne muscular dystrophy, fragile X). Among the controversies are the question of informed consent, whether to disclose incidental discoveries such as carrier status, whether an efficacious treatment must exist, and when to screen universally or target testing to particular populations. Several unique features of NBS apply to infants in the neonatal intensive care unit (NICU), and NBS can employ technologies other than the Guthrie card (eg, hearing screening).