The Cathedral of the Annunciation was built by architects from Pskov in 1484-1489 as part of Grand Duke Ivan III's plans for a large-scale renovation of the Moscow Kremlin.

After being badly damaged in a fire in 1547, the then Grand Duke (and subsequently first Russian Tsar) Ivan the Terrible began a restoration of the church, which was completed in 1564 Many of the church treasures were lost during the occupation of Moscow by the armies of the Polish–Lithuanian Commonwealth in 1612 at the close of the Time of Troubles.

From the time of Ivan the Terrible's coronation as tsar, the members of the royal family worshiped at the Annunciation Cathedral, got married and baptized their children there.

The interior of the cathedral consists of the central prayer area and several surrounding galleries, with the additions of side altars in the 16th century.

Behind the altar (where once the sacristy was located) a large silver reliquary containing the remains are of about 50 saints from different places in the Middle East was discovered in 1894.