It is often assumed that humoral theory remained unchanged and the dominant medical theory throughout the pre-modern history of Islamic societies. Historians have provided various explanations for this persistence of humoral theory ranging from the (alleged) religious prohibition against dissection to a predisposition amongst medical writers towards systematizing and summarizing rather than critical inquiry. Some have even claimed that Avicenna’s categorization of medicine as an applied natural science prevented the overthrow and/or modification of humoral physiology since any investigation of its principles, by virtue of being a part of Physics, was off-limits to physicians qua physicians. Yet, writers engaged critically with medical theory in their commentaries on the Canon of Medicine. The leading figure in this critical engagement was Ibn al-Naf?s (d. 1288). In this paper, I examine how the genre of medical commentaries on Avicenna’s Canon began to challenge specific aspects of humoral theory and its concomitant understanding of digestion beginning with Fakhr al-D?n al-R?z? (d. 1209). Al-R?z?’s philosophical challenges were taken up by subsequent commentators, ultimately leading to Ibn al-Naf?s’s claim that blood was the sole nourishing humor. Ibn al-Naf?s provided philosophical and empirical arguments for his critique of the Galenic physiological and anatomical understanding of digestion, and in support of his new proposals. The paper thus provides evidence for the vitality of the post-classical commentary tradition, and reveals the important role played by empirical anatomical observations in medical commentaries.