Why do some regions and territories perform systematically better than others in terms of economic development and wealth? What are the key drivers of local and regional economic and innovative performance? This talk will challenge the ‘traditional’ answers to these questions based on ‘linear’ models of innovation and regional growth. Conversely, the talk will present an eclectic approach to the territorial genesis of innovation and regional growth by combining different theoretical strands into an ‘integrated framework’. This integrated approach will make it possible to single out the territorial drivers of innovation and growth and their spatial interactions. Practical examples will come from the assessment of the impact of infrastructural investments in Europe and from the case study of the Lazio Region in Italy.