Over the past 50 years, University-Industry (UI) relationships have evolved dramatically, becoming increasingly important for driving innovation, national competitiveness, and economic growth. This chapter explores how these relationships have transformed through the twentieth century alongside major shifts in innovation processes, the system-wide organization of R&D and innovation, policy and legal frameworks, and public spending on R&D. It charts the growth in scale and scope of UIRs, the increasing importance of relation-based interactions, the (re-)emergence of dedicated innovation and economic development missions for many universities, and the many factors influencing the process. It concludes by setting out what needs to be done to unleash even more value from these important relationships, highlighting new incentives able to attract and retain a broader range of expertise, new partnership approaches and organizational spaces, and a focus on building local innovation ecosystems. An emphasis on finding ways to better integrate research, solutions development, workforce development, and system development is also needed to accelerate the development of solutions to large complex challenges.