The paper aims to support regional policy-makers who seek to understand the determinants of regional innovation dynamics. The challenge is to penetrate the black box of the RIS (Regional Innovation System) by identifying the building blocks and interaction processes that stimulate innovation at the regional level. Thanks to a creative database, the main originality of this study is to analyse regional innovation as a process of competences building. To test this explanatory model, a Knowledge Production Function is estimated at the regional level in France by using a simultaneous equations setting. Our results validate the systemic dimension of regional innovation and identify the most valuate input-output transmission mechanisms.