In recent years, regional innovation policies across Europe have relied on the smart specialisation approach to support new path development. However, its focus on endogenous knowledge flows remains a major weakness of the approach. This article argues that smart specialisation has to adopt an outward-looking approach that combines knowledge flows external and internal to the region. Based on four stylised types of regions, the article proposes generic strategies that can be pursued through smart specialisation. In terms of its policy implications, the article argues that policymakers should develop their regions’ external connectedness strategically to leverage complementarities in global knowledge flows for new path development.