Occasional references to the ancient Pyrrhonists can be found throughout the late Roman and early medieval periods. The oldest extant Greek manuscript of Sextus dates from the tenth century, and manuscripts of Latin translations existed in medieval collections by the fourteenth century. More manuscripts came into Italy from Byzantium in the mid-fifteenth century, when the Florentine religious leader Girolamo Savonarola (1452–1498) used Sextus to combat pagan philosophy, and the humanist scholar Pico della Mirandola drew on Sextus to fight other dogmatists. Knowledge of the materials eventually spread into France and other northern countries.
The printing press made for the most influential dissemination of these texts. Published Latin translations by Henri II Estienne (Stephanus) (1562) and Gentian Hervet (1569) provided the stimulus for a widespread "skeptical crisis." Michel de Montaigne (1533–1592) was the most influential of the early European writers to draw on the writings of Sextus in his Essais (Essays; 1580–1595). In his longest essay, "Defense of Raymond Sebond," Montaigne retailed most of the skeptical tropes and all of the skeptical vocabulary from Sextus Empiricus. In this and other essays he demolished pretensions to human knowledge and argued both sides of nearly all issues. He was never pessimistic but showed people how to live a good life in spite of skepticism, which helps explain why his work was so popular.
Later thinkers often started from Montaigne. One who went beyond him in posing questions of skepticism was René Descartes (1596–1650). Without specific precedent in the ancient materials, he set out to answer the skeptical idea that there could be an all-powerful malin genie or evil demon that manipulates human perceptions and reasoning, fooling people about the world. His conclusion was that individuals know of their existence because they can think—the famous "I think therefore I am." Explaining why one's perceptions of thinking could not be a deception, Descartes asserts that God would not allow such deception. Religion is invoked to certify truth. Later skeptics would worry about a deceiving God.
Bishop Pierre-Daniel Huet (1630–1721) and the Huguenot refugee Pierre Bayle (1647–1706) have been described as the "master skeptics." Huet invoked Sextus Empiricus in great detail against Descartes and many other dogmatic philosophers in his Traité philosophique de la foiblesse de l'esprit humaine (1723; Philosophical tract on the weakness of the human mind). Bayle's massive works attacked all previous philosophy and historical scholarship but upheld moral rigorism.
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