This chapter begins with a discussion of the most significant painting of the Antichrist in Western art – Luca Signorelli’s ‘The Sermon and Deeds of the Antichrist’. This painting is located within the story of the Antichrist in the Italian Renaissance, particularly around Girolamo Savonarola. With the Reformation, a new chapter in the life of the Antichrist began. Within Protestantism, the papal Antichrist (both individual and as an institution) became dominant. The views of Martin Luther, John Calvin, and John Knox are discussed, along with representatives of the so-called Radical Reformation, both on the Continent and in England. Key to the Protestant reading of the pope or the papacy as the Antichrist was a new interpretation of the book of Revelation that reinforced the judgement that the Antichrist was to be found in the Roman papacy and had been present there since its inception. The chapter analyses the new Protestant interpretation through the commentaries on Revelation by John Bale and John Napier. The chapter also examines the Catholic response to Protestantism by a return to the Antichrist of Adso of Montier-en-Der.