The Sack of Rome (1527) caused unimaginable human suffering and material damage. More serious for the Roman Church was the profanation of the city at the hands of an army that, though serving a Catholic monarch, included a substantial Lutheran element, which perpetrated a systematic assault on relics and sacred images. Beyond the restoration of the physical fabric of Rome, the Church's response to the Sack involved the visible resanctification of the city as an encyclopaedic representation of a transcendent order. This required a profound confrontation with the sharpening scruples of reformers about pilgrimage cults and the use of images in worship.

The Sistine Last Judgement (1534-1541), as rethought by Michelangelo during the early years of Paul III, constitutes a central instrument of such a response. The selection and positioning of major figures in the painting suggest a diagrammatic image of Roman sacred topography. The few identifiable saints relate to the Church's pastoral role and institutions of welfare at a time of deepening need in the city (one important response was the early ministry of Ignatius of Loyola, in Rome from 1537). The emphasis on patron saints of key Roman industries/crafts is consistent with the importance of artisan confraternities in the Church-sponsored development of popular religiosity at Rome; this may resonate with the unprecedented and paradoxical treatment of the saints' attributes as instruments of martyrdom actively wielded by the saints themselves. This too relates to the Church's response to Lutheranism, specifically the revaluation of labour and the workaday world.

Michelangelo's painting, finally, occasioned a fierce debate about religious imagery; in part it fell victim to it. The debate is anticipated in the painting itself, which gives prominence to saints, notably Bartholomew, who perished for their assault on image worship. Such iconoclastic associations are related to the central paradox of the painting; the coexistence of conspicuous fictive elements (not only the much criticized Dantesque figures) and devices that deny the factivity of the work. This, finally, leads to the problem of the celebrated skin displayed by St. Bartholomew. It is not his own skin, but a mere simulacrum, its sign character frankly manifested. This is its official aspect; more personally, the features of Michelangelo on the skin resonate with his poetic expressions of doubt about the value of his art, as if to deflect or even expiate criticism of artistic hubris in the face of the awful second coming of Christ as universal judge.