The United States Food and Drug Administration (FDA) was expected to approve 60 breakthrough cell and gene therapies over the next 10 years, highlighting the urgent need to upgrade the newborn screening (NBS) system. Expert stakeholders were brought together for the study to examine the NBS system’s issues and provide recommendations for its modernization. About 1 of 5 mixed-stakeholder panel discussions included NBS stakeholders (researchers, clinicians, state NBS leaders, advocates, industry experts, and current/former advisory committee members). Participants took a survey before the panels in which they read and assessed NBS issues derived from relevant literature. During the discussions, participants discussed difficulties and possible solutions. The results of the pre-panel survey were evaluated descriptively. A brief qualitative analysis was used to examine the data from the panel talks. The top 3 most significant barriers to address, according to the median scores of the ranked challenges (1=most substantial), were critical missing data for NBS decision-making (Median=2), the burden on state NBS laboratories (Median=3), and the amount of time required for the state-level implementation of screening for new conditions (Median=4). The infant’s well-being should be the focal point; the transformative therapy pipeline, while undeniably beneficial to individuals with rare diseases, poses a threat to NBS capacity; decisions about modernizing NBS should be evidence-based; additional financial support is required but not sufficient for modernization, and modernization will necessitate participation of multiple NBS stakeholders. The third broad subject was discussed in detail, covering the challenges that NBS faces in terms of competence, coordination, and collaboration and creative approaches to oversight, partnership, and coordination proposed by participants. Representatives from various stakeholder organizations were brought together for this study to develop potential answers to the issues that NBS is facing in the United States. These solutions offer policymakers and other stakeholders a strong starting point for maximizing the impact of new transformational therapies on babies, families, and society.