Trends in regional disparities phenomenon are a major problem in regional economics for many decades. Significant initial differences between regions affect development capacity of each of them and response to external challenges posed by globalization, and also their ability to enhance competitiveness and international trade. Thus, identifying ways to overcome them is essential for regional policy decisions. The challenges of integration and economic development, although defies simple solutions, should not consider a complex guiding principle, but an appropriate mix of policy intervention. At present, the debates on geographical disparities of economic development begin and end with taking into account the spatially targeted interventions, using as instruments: innovation, infrastructure and institutions, in supporting the transition to the “cities of tomorrow”: dynamic, attractive, inclusive and careful about environmental issues. Therefore, this paper aims at analyzing the evolution of the phenomenon from the perspective of the main tools to improve it in the current macroeconomic context that strongly affects the enlarged European Union.