Very little is known about Aenesidemus's life. He was associated with the Athenian Academy around the time of its collapse in 87 BCE; and he was party to the dispute between Philo of Larissa, who advocated a mild form of skepticism in the form of an externalist, coherentist epistemology, and Antiochus of Ascalon, whose epistemology was basically that of Stoic foundationalism. The Academy had been for two centuries the home of epistemological skepticism, directed largely against the optimistic epistemology of the Stoics, who posited "apprehensive impressions" (phantasiai katalêptikai), which carried their own guarantee of truth. Aenesidemus saw Philo and Antiochus as betraying that heritage, as "Stoics fighting with Stoics" (Photius, Library Catalogue 212), and resolved to "philosophize after the fashion of Pyrrho."

Aenesidemus wrote eight books of Pyrrhonian Discourses, which Photius summarized: "the whole aim of the book is to ground the view...