<b><i>Background:</i></b> Newborn screening program (NBS) is a vital public health service aiming to prevent morbidity, mortality, and disability through early detection and intervention. The service is a complex system that requires proper communication between its different constituents. The advent of technology in this field represented by the existence of robust analytical diagnostic tools which allow for rapid analysis of many rare congenital disorders along with the accelerated revolution of health information technology is a capstone towards improvement of an individual’s life quality and patient safety enhancement. <b><i>Summary:</i></b> Effective screening program requires an effective system that delivers results in timely manner, tracks those who are affected, and shares long-term outcomes at population level. Recently, more focus has been placed on the implementation of long-term follow-up (LTFU) data systems as an effective tool for continuous evaluation of the efficacy of NBS program. The ability to communicate health information using health information exchange system (HIE) is very essential to effective implementation of any LTFU plan. <b><i>Key Messages:</i></b> This review explores other programs’ experience in the impact of implementing HIE system in relation to LTFU data system in the era of NBS program and the importance of having a well-established collaboration infrastructure. Also, and at a glance, the current status of the Saudi National NBS program in the context of health informatics and barriers faced towards implementation of successful LTFU data system in relation to HIE is highlighted. Future trends may involve incorporating genomic data to LTFU system allowing for the application of the newly emerged personalized medicine era.