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This paper contributes to the climate policy discussion by focusing on the challenges and opportunities of reaching net zero emissions by 2050 in Italy. To support Italian energy planning, we developed energy roadmaps towards national climate neutrality, consistent with the Paris Agreement objectives and the IPCC goal of limiting the increase in global surface temperature to 1.5 °C. Starting from the Italian framework, these scenarios identify the correlations among the main pillars for the change of the energy paradigm towards net emissions by 2050. The energy scenarios were developed using TIMES-RSE, a partial equilibrium and technology-rich optimization model of the entire Italian energy system. Subsequently, an in-depth analysis was developed with the sMTISIM, a long-term simulator of power system and electricity markets. The results show that, to achieve climate neutrality by 2050, the Italian energy system will have to experience profound transformations on multiple and strongly related dimensions. A predominantly renewable-based energy mix (at least 80–90% by 2050) is essential to decarbonize most of the final energy consumption. However, the strong increase of non-programmable renewable sources requires particular attention to new flexibility resources needed for the power system, such as Power-to-X. The green fuels produced from renewables via Power-to-X will be a vital energy source for those sectors where electrification faces technical and economic barriers. The paper's findings also confirm that the European "energy efficiency first" principle represents the very first step on the road to climate neutrality. [ABSTRACT FROM AUTHOR]