The growing interest to address societal challenges is changing research and innovation policy dynamics. However, a challenge-oriented approach requires specific public sector capacities to coordinate and provide directionality while having an innovation ecosystem with sufficient scientific and technological endowments to address them effectively. In this perspective, a challenge-oriented policy is not a one-size-fits-all approach, and only recently, the literature has started investigating these territorial differences. This paper proposes a composite index to assess REgional Societal Challenges-Oriented REadiness (RE-SCORE). An exploratory application is conducted to examine and compare Italian regions facing four selected societal challenges (SC)s: bioeconomy, climate change, health, and inclusive, innovative and reflective societies. The findings show that the Italian regional readiness in addressing SCs is highly heterogenous, beyond the ‘traditional’ North-South divide. The index allows to benchmark regional capacities for comparative analysis and identify possible interregional synergies around specific SCs. This approach could be used in other European countries and at the European level to assess the regional readiness to tackle SCs. Gaston Heimeriks, Utrecht University has been involved as discussant.