Newborn screening (NBS) includes biochemical testing for certain medical conditions that can cause devastating consequences if left undetected and untreated. Mandated screening requires a complex support system to ensure its effectiveness. There are 51 separate NBS programs in the United States, all with different administrative structures and screening panels. Only 8 states mandate screening for cystic fibrosis (CF) and 2 of these are just beginning. Optional NBS for CF reaches significant numbers of newborns in 3 other states but the CF screens are only projected to reach about 20% of the newborn population in 2005. Forthcoming recommendations for NBS screening from the federal Advisory Committee on Heritable Diseases and Genetic Disorders in Newborns and Children (ACHDGDNC) will impact decisions about NBS panels and professional and consumer advocacy will play an important role in deciding the directions in which NBS programs move. For effective CF NBS, CF care centers will need to partner with NBS programs to ensure optimal health benefits, and programs will need to continually evaluate diagnostic and outcome data in order to refine their screening protocols.