It was in 1516 Francis I brought Leonardo da Vinci to the Château de Cloux and installed him there, again on the advice of his sister, Marguerite de Navarre. Leonardo da Vinci traveled across the Alps, carrying with him on muleback three of his most remarkable paintings. These were the Mona Lisa, St. Anne and St. John the Baptist, which he completed at Le Clos Lucé. A pension of 700 golden Ecus a year was granted him by the king and Leonardo was "free to think, dream and work". Leonardo da Vinci was treated with real affection by Francis I who called him "my father", his sister Marguerite and the whole Court. He found a very special inspiration there, which he passed on to his disciples, while teaching them his techniques. He did his utmost to pass on his knowledge to them until the end of his life.

A multidisciplinary genius, Leonardo da Vinci made some extraordinary scientific discoveries and invented machines that were four centuries in advance. Leonardo's first interest was in the military domain, studying arms and machines of war. It seems he was the first to have had the idea of a submachine gun, at the time of the siege of Florence by the pontifical troops in 1470.

His studies extended to numerous domains, such as hydraulics, mechanics and aeronautics. After having observed birds for a long time and studied their flight, Leonardo constructed a sort of glider with articulated wings inspired by the wings of a bat. He imagined also the principle of the parachute and vertical elevation by an inclined fan blade, anticipating the helicopter.

In the model gallery at Clos Lucé, the 40 machines of Leonardo da Vinci are exhibited, reconstructed by IBM after the drawings of the genius, amongst which figure the first car, the metric counter, the paddle steamer and the double-hulled vessel.

Leonardo da Vinci carried out various commissions for the king as designer of Court festivals, architect, civil engineer (studies for the Canal de Romorantin, locks on the Loire), military engineer, town planner, advisor.