The Handbook contains chapters on the organization of innovative activities across borders, the location of innovation, the role of alliances and networks and the impact of the internet on managing global innovations. Some of the contributions to this Handbook focus on large multinational firms investigating issues such as subsidiary innovation initiatives, or the role of corporate governance as a boundary condition to the relationship between innovativeness and internationalization. We also introduce a critical take on the institutional support offered within EU to internationalizing SMEs and suggest ways to improve the current status quo. We reveal interesting insights into decisions to offshore innovation activities by medium-sized enterprises and tackle the phenomenon of digital outsidership, which is particularly relevant in a post-COVID-19 world and can be disadvantageous for European internationalized SMEs unable to implement digitalized business models. At a supra-national level, we focus on EU regulations as a facilitator (inhibitor) of innovation.