Severe combined immune deficiency (SCID) has been identified as a disorder of high priority for population-based newborn screening. Most affected infants are not brought to medical attention until they develop serious infectious complications, and SCID is fatal if untreated. Effective treatment with allogeneic hematopoietic stem cell transplantation is widely established. The best outcome for SCID, as with many other conditions for which newborn screening is now done, is achieved if hematopoietic stem cell transplantation is performed in the first months of life, ideally before clinical presentation with infections and failure to thrive. A meeting in San Francisco in May 2007 brought together experts from newborn screening programs; the pediatric immunology community; pediatric transplant centers; and federal, state, and nongovernmental agencies to consider obstacles to and implications of developing newborn screening for SCID. Development of an appropriate low-cost, high-throughput screening algorithm has been a challenge, although absence of T-cell receptor gene excision circles is a sensitive marker of profound T lymphocytopenia and currently is the most developed screening method. A consensus was reached on several points: SCID newborn screening should be pursued with pilot studies in key locales, test methodologies need to be optimized, screening programs must be integrated with plans for definitive diagnosis and management, centralized specimen banks and registries are required to foster test validation and track outcomes that will guide future treatment, and SCID newborn screening will lead to important knowledge about human immune disorders as well as better care of patients.