The historiography of Western folly has projected the Renaissance as an age uniquely tolerant of and interested in irrationality, taking the humanist ‘praise of folly’ literature as a marker of this openness. This article problematizes such a representation of Renaissance humanism by exploring the discourse of ‘naturals’ rather than of artificial fools who are at the heart of humanist celebrations of folly. By focussing on legal, medical and New World debates on natural fools, ‘monsters’, wild men, ‘savages’ and natives, this article reveals not just an ambivalence towards fools but also deeper contradictions within Renaissance humanism. The article points out continuities between medieval scholastic, Renaissance humanist and Enlightenment discourses of folly, seeking to provide a caveat against both traditional and Foucaultian historiographies which regard the Renaissance as being singularly hospitable to mental deviance. This article also identifies the persistence of certain tendencies in the discursive practices of folly, finding echoes of Renaissance discussions in later debates in the field of mental disability and the history of psychiatry.