Skepticism is both a tool and a threat for Gassendi. Richard Popkin's characterization of Gassendi and Mersenne as mitigated or constructive skeptics – thinkers who reject Aristotelian scientia and its claims to know essences on the one hand and the skeptical claim that nothing can be known on the other – is well known. It captures an important aspect of Gassendi's thinking, especially in his early works. However, in this as in so many other matters, there is a development in Gassendi's thinking. The early Exercitationes, Popkin's chief text, emphasizes skepticism as a weapon against Aristotelianism. In contrast, the system of canonic provided in the Syntagma outlines a positive program for achieving knowledge, one that responds to Gassendi's earlier skepticism.

In La vérité des sciences, Mersenne uses Pyrrhonist arguments to undercut chemists and other opponents of “the Christian Philosopher, ” while rejecting Pyrrhonism about knowledge in general. His chief strategy against an overarching Pyrrhonism is to place strict limits on the scope of the certain – allowing only mathematics and the articles of faith to count – and to construe the majority of natural philosophy as merely probable. Similarly, Gassendi uses Pyrrhonian techniques to rebut Aristotelian metaphysics and physics. At the same time, he carefully limits the scope within which Pyrrhonism can legitimately be deployed. This tactic is evident as early as the Exercitationes.