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This review of newborn screening examines the beginning of screening with the story of phenylketonuria and explores the principles of screening and the criteria with which disorders were added to newborn screening panels. The explosion of tests that are screened for followed the adoption of tandem mass spectrometry (MS-MS) technology. The inequity of state newborn screening panels was brought to the forefront with an American Academy of Pediatrics task force report in 2000 that called for a national panel. The American College of Medical Genetics convened an expert panel to produce such a panel. In 2006, they published their panel of disorders, recommending a panel of 29 core disorders and 25 additional secondary targets. Ethical arguments about newborn screening have resurfaced with the recent expansion of testing that include arguments about consent, mandatory participation, benefits to those screened, and cost—both to the individual and society. Finally, the future direction of screening is discussed. Newborn screening is undergoing rapid expansion. The addition of tests involves ethical, financial, and social pressures.