In the first decades after the founding of the modern Roman Inquisition in 1542, Girolamo Cardano was the most prominent natural philosopher to face imprisonment and trial. A trove of Inquisitorial letters, decrees and censurae have survived, offering a detailed picture of how, in the early years of its existence, the Roman Inquisition placed theological boundaries around astrology and natural philosophy. This article will cover the trial and identify a critical point of contention: that Cardano allegedly naturalized heresy. It will suggest that we view the Cardano affair as a reaction against a natural philosophy threatening to constrain the Inquisition’s right to judge enemies and execute that judgment. Finally, this article will discuss how, in light of the Inquisition’s reading, we might consider Cardano’s astrology to accommodate Christian doctrine.