In 1500 to 1510, under Ludovico Sforza, the octagonal cupola was completed, and decorated in the interior with four series of 15 statues each, portraying saints, prophets, sibyls and other characters of the Bible. The 349 ft spire is known as Guglietto dell'Amadeo ("Amadeo's Little Spire"), constructed 1507-1510.

The Gothic cathedral took five centuries to complete and is the fourth-largest church in the world. In 1386, Archbishop Antonio da Saluzzo began construction in a rayonnant Late Gothic style more typically French than Italian. There is a long list of master builders who served as head of the Fabbrica del Duomo (created 1387), beginning with Simone da Orsenigo. The Fabbrica employed foreign architects as well, French and German, including Nicolas de Bonaventure (designer of the apse windows) and Heinrich von Gmünd (of the Parler family). July 1391 the Italian architect and painter Giovannino de Grassi was appointed engineer of the Fabbrica and produced a wide range of works including the design of the pier capitals. On May 20, 1805, Napoleon Bonaparte, about to be crowned King of Italy, ordered the façade to be finished; finally within seven years, the facade was finished, following a 17th century Neo-Gothic plan by Carlo Buzzi.