Science, technology, and innovation (STI) are directly linked with prosperity in today's global, competitive, fast-paced, and knowledge-based economy as they are not critical for the industrial development only, but also have a direct impact on the living standards. Therefore, a properly functioning innovation system is the key to permanent progress, from the perspective of both economic growth and development. This chapter lays out the national system of innovation (NSI) approach and accentuates the role of the government within that regard. As an example for a successful model, the U.S. innovation ecosystem is examined with an historical background both from the public policy perspective and at the institutional level through practical applications, particularly within the concept of university-industry collaboration. Also in the light of today's swiftly growing digital technology and global competition, the system of innovation is revisited to make assessments for future sustainability.