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In this study, trends and relations of Europe 2020 target indicators on Inclusion and Smartness at region level, with particular attention to the area of Mezzogiorno of Italy, have been analysed. First of all, causal relations between the indicators on poverty, employment, education and research of the Europe 2020 Strategy have been investigated. Then, in order to measure the progress of the European Countries and of Italian Regions towards the strategy’s objectives, a “distance-to-target” approach (European Union, 2014), has been applied. This tool allows to quantify regional quality of life in terms of distance from specific targets, identified by the Europe 2020 strategy, considering indicators of Smartness and Inclusion. Therefore, a “distance-to-target” value has been calculated for the relevant indicators, using the EU headline targets for both levels of analysis (regional and national), since the Europe 2020 process has not yet specified regional targets. Finally, a composite indicator has been constructed, with the aim of comparing different areas and their progress towards the targets. The results of this analysis show that many regions of the Mezzogiorno of Italy are performing badly for the Smartness and Inclusion Indicators. For example, poverty and social exclusion is highest in Sicily (IT), Campania (IT) and Calabria (IT) with values above 32% together with Canary Islands (Spain) and North-East Romania.