In recent decades many structural and institutional changes have reshaped the economic and social European landscape. The ongoing industrial restructuring from the 1970s, the new technologies, the globalization process, the neoliberal paradigm and the European integration were major drivers of this reshaping. One of the intriguing trends from the past four decades is the evolution of regional disparities. The evidence of the increasing regional disparities in parallel to the deeper EU integration presents a challenge both for economic growth theories and for policy makers. The increasing disparities in growth rates across European countries and regions, especially since the Great Recession, has reopened the debate concerning regional disparities and the drivers of regional growth. This chapter discusses the Economic and Monetary Union (EMU) regions from the introduction of the Euro to the present, focusing on features of the regional innovation system to explain the economic growth.