Policy decisions for newborn screening (NBS) are particularly challenging when the balance of benefits and risks is not tipped dramatically in 1 direction. When this is the case, as with cystic fibrosis (CF), the traditional approach of mandatory testing of all newborns in all states may not be appropriate. Alternative approaches may produce a substantial reduction in psychosocial risks, at the cost of a small reduction in medical benefits, and thus improve the benefit/risk balance. At the provider level, this could include greater engagement and discussion with parents before testing. At the program implementation level, specific decisions about tradeoffs between sensitivity and specificity that could result in not identifying all infants with CF may be appropriate. At the policy decision level, deciding whether to implement CF NBS in a particular state could involve consideration of the availability of the financial resources, clinical services, and systems for assessing outcomes. Although CF NBS can be justified in settings in which the specific approach has a favorable benefit/risk balance, an inadequately designed screening program has the potential for being less favorable than the current approach of diagnosis on the basis of clinical criteria or family history.