This essay explores a familiar concept from the philosophy of science—underdetermination—in an unfamiliar context: explanation. Underdetermination is usually deployed in the realism debate, or in discussions of theory confirmation. Here, instead, I am concerned with how underdetermination, interpreted as the necessity of background assumptions, can help us understand a specific historical case involving a dispute about explanatory success. In particular, I look at the work of William Harvey, discoverer of the circulation of the blood, and his rejection of materialist modes of explanation in the course of his De generatione animalium (1651). I articulate the nature of three background assumptions at work here, which affect Harvey's conception of: (1) how to explain; (2) what to explain; and (3) the larger explanatory stakes.