The main goal of this paper is to propose a sound interpretative and policy framework for ‘Inner Peripheries’ at the EU level. Its ambition is to bridge conceptual approaches to peripherality with the policy objectives set by key documents such as the Territorial Agenda 2020 and other recent reports on economic, social and territorial cohesion. An integrated multi-scalar approach, grounded on the notion of spatial disparity, is therefore connected with a ‘place-based’ approach to policy design. The breakthrough experience of the Italian programme on Inner Areas is an opportunity to broaden the reflection on inner peripheries and policies that are most apt to reconnect them. A more comprehensive analytical framework is proposed here, which looks at the foundational economy, spatial justice and territorial cohesion. The framework deals with both the ‘condition’ of peripherality and the ‘process’ by which endogenous and exogenous drivers determine the marginalisation of specific territories. Such tenets are fleshed out in the development of an original approach bridging theory and practice, analysis and policy, crucially assuming multi-scale governance design as the enabling framework for greater coherence between top-down and community-led initiatives.