Between 5000 and 8000 rare diseases (RDs) affect the daily lives of around 30 million people in the EU, representing a significant challenge for the healthcare system and society. RDs patients often experience long and burdensome path to diagnosis, possible misdiagnosis, or improper treatment, which may be due to low prevalence of RDs, high number of different diseases and the lack of general sensibleness. It is estimated that 72% of RDs are genetic and 70% have an exclusively paediatric onset. Strategies for genetic newborn screening (NBS) are thus of pivotal importance, since an early RDs diagnosis would radically change their clinical history. Screen4Care (S4C), a new EU Research Project, is a public-private collaboration of 35 partners led by the University of Ferrara and including 21 academic partners, 9 industrial project partners -led by Pfizer-, 4 small and medium-sized enterprises and EURORDIS. S4C -that will last five years- offers an innovative research approach to accelerate rare disease diagnosis, through two central pillars: genetic NBS and artificial intelligence (AI)-based tools such as machine learning. The first central pillar, genetic NBS, will adopt different strategies interrogating: I) currently treatable RDs (TREAT-panel-approach), II) actionable RDs (ACT-panel-approach); III) and whole genome sequencing (WGS) will be offered to symptomatic patients when NBS resulted negative. Moreover, S4C aims to use the power of innovative digital solutions to shorten time to diagnosis via two routes: I) predictive algorithms, leveraging the Screen4Care data (federated) machine learning environment and embedded electronic health record (EHR) systems; II) a repository of AI "symptom checkers", which will be designed to facilitate self-diagnosis and/or to suggest referral pathways to physicians for diagnostic workup. S4C aims to shorten the path to RDs diagnosis with this dual approach and to establish a digital infrastructure for families and health workers.