The energy scenarios were developed using TIMES-RSE, a technology-rich partial equilibrium and optimization model of the entire Italian energy system. Subsequently, an in-depth analysis was developed using sMTISIM, a long-term simulator of the energy system and electricity markets. The results show that, to achieve climate neutrality by 2050, the Italian energy system will have to undergo profound transformations on multiple and strongly correlated dimensions. An energy mix predominantly based on renewables (at least 80-90% by 2050) is essential to decarbonize the majority of final energy consumption. However, the sharp increase in non-programmable renewables requires particular attention be paid to the new flexibility resources needed for the electricity system, such as Power-to-X. Green fuels produced from renewable sources through Power-to-X will be a vital energy source for those sectors where electrification faces technical and economic barriers. The results of the paper also confirm that the European principle of ‘energy efficiency first’ is the first step on the road to climate neutrality.