In 2018 and 2020, the major Space Agencies in the world published the Global Exploration Roadmap (GER), where they shared the common intent to expand the human presence into the Solar System with the surface of Mars as a driving goal and the Moon as a necessary intermediate step. About 30 robotic and 4 crewed space missions to the Moon (from 13 Countries and from both Space Agencies and private companies) have been already approved to be launched in the 2021 – 2028 time frame, while ~ 20 more missions are under evaluation. The goal of this space effort is to establish a sustainable human presence on the Moon and, in the future, also on Mars. This seminar will discuss the strong effort ongoing worldwide and the important opportunities that could be offered in several sectors of science, technology, economics. The return to the Moon will revolutionize the relation of mankind to Space exploration. Experiments and facilities on the Moon, including new structures and devices for the observation of the Earth and the Universe, will boost planetary science, life science, physiology and medicine, radio, optical, infrared and cosmic ray astronomy, and more. The Moon has the potential to become the test ground for human capability to survive and operate in space, as well as a launch base for future planetary missions. The role that Italy is playing in this context and the one it could play in the next future will be also discussed, with emphasis on ideas and proposals coming from its scientific community.