Smart specialisation is currently probably the largest innovation policy experiment in the world. Its aim is to move the EU less developed countries and regions on path of R&D-based growth. This transformation requires not only endogenous knowledge and technology accumulation building but also coupling with international knowledge and production networks. Yet, internationalisation does not seem to be a crucial component in the design and development of Research and Innovation Strategies for Smart Specialisation (RIS3), which are at odds with the strong dependence of the EU New Member States (EU-13) on FDI and global value chains. Our analysis is grounded in the key ‘stylised facts’ related to EU-13 R&D&I activities, and the complex link between innovation and internationalisation. Innovation systems in the EU-13 are fragmented and based on largely public R&D systems and on predominantly production-oriented foreign direct investment (FDI). This structural weakness calls for stronger support for innovation-oriented activities and for the integration of global value chains (GVCs) and FDI into local innovation systems. We explore the main obstacles to the internationalisation of smart specialisation and discuss ways to overcome them. We highlight the policy action areas related to providing support for technology upgrading in relation to the internationalisation of smart specialisation.