After Leonardo's death in 1519 Francesco Melzi, his favourite pupil, brought many of his manuscripts and drawings back to Italy. This is confirmed by a note written by an agent of the Duke of Ferrara, dated 1523, referring to: "those little books by Leonardo about the anatomy, and many other interesting things", a fact mentioned also by an early sixteenth century source, the "Anonimo Gaddiano", in regard to the inheritance left by Leonardo to Melzi, which included: "cash, clothing, books, drawings, painting instruments and portraits". Fortunately, of Leonardo's vast output, over five thousand pages of drawings and notes have come down to us, in his characteristic "mirror-image" hand-writing, running from right to left. But this huge mass of writings, undoubtedly the largest collection of the entire Renaissance, has endured many vicissitudes following Leonardo's death. In fact, Leonardo's manuscripts are today nothing like the way they appeared and were grouped together during his lifetime, or even when they passed into the hands of his faithful disciple, Francesco Melzi. It was Melzi's heirs who, after his death in 1579, began to scatter the material. Having no idea of their importance, they initially stored Leonardo's drawings and manuscripts in a loft, later giving parts of it away or selling sheets cheaply to friends and collectors.

Already in 1630, the Barnabite Antonio Mazenta speaks of the dispersal of the Leonardo manuscripts, and singles out Pompeo Leoni, a sculptor at the court of the King of Spain, as one of those chiefly responsible not only for losing part of the collection, but even worse, for rearranging the order of its contents. Indeed, in an effort to sort the artistic drawings from the technical ones, and to put together the scientific notes, he split up the original manuscripts, cut and pasted pages and created two separate collections. One is now called the "Codex Atlanticus", the other the Windsor collection, which contains some six hundred drawings. Using the same method, Leone went on to create at lest four more volumes. Upon Leoni's death, his heirs brought part of the manuscripts back to Italy, where they were purchased by Count Galeazzo Arconati who, in 1637, donated them to the Ambrosiana Library where they remained until 1796, the year of Napoleon Bonaparte's arrival in Milan. Napoleon ordered the manuscripts to be transferred to Paris, but in 1851 the Austrian government requested their return. Only the Codex Atlanticus was actually returned, while the other twelve manuscripts, marked with the letters A to M, remained in Paris, and were regarded as lost. Other manuscripts stayed in Spain and then went their different ways.

Others remained undiscovered until 1966, when they were found quite by chance in the archives of the National Library of Madrid. The current Codex Leicester (formerly Hammer) is instead one of the manuscripts which Melzi did not inherit and which, curiously, strayed from the path of most of the other Leonardo notes and today is the only manuscript to be found in private hands. Studies on the Leonardo manuscripts were only embarked upon systematically towards the mid-19th century; around the turn of the century these investigations led to the establishment of the "Vinci Royal Commission"; the aim of these painstaking studies and transcriptions was to reconstruct the original arrangement of the manuscripts. The first public exhibitions of Leonardo's scientific and technological works dates back to this period.