Social and regional cohesion are central concerns of the European Union. According to the dominant neoclassical perspectives, the neoliberal form of integration, with the single market at its core, together with regional policy are assumed to contribute to prosperity and development and eventually lead to cohesion in Europe. However, large disparities still exist in Europe. Moreover, the crisis which started in Europe in 2008 has led to increasing regional and national inequality. The chapter therefore questions the dominant neoliberal assumptions about regional development and cohesion and provides an alternative theoretical framework which helps do understand why regional and national inequalities are increasing in Europe. In the tradition of critical political economy uneven development is recognized to be a key aspect of capitalism. Thereby, specific concepts developed by the dependency approach and regulation theory are used to understand the asymmetric relationships and the dependency structures between the core and peripheral countries and regions in Europe. Based on this, conclusions regarding strategies to overcome regional and national inequality in Europe are drawn.