In the past decades the Three Rs concept, famously launched by Russell and Burch in their 1959 book The Principles of Humane Experimental Technique, has gained a prominent place in the landscape of societal and ethical concern about animal use. Important scientific and institutional initiatives have been taken in order to promote replacement, reduction and refinement. It appears, however, that conceptual and ethical thinking about the presuppositions and changing contexts of the Three Rs concept has lagged behind the scientific and practical efforts. In this paper, first, I argue that there is a threefold argument to make for the need to reconsider the moral basis of the Three Rs concept. Second, I outline a number of standard assumptions of the traditional approach to the Three Rs and question the tenability of these assumptions. Third, I propose some elements of a new framework for the Three Rs principle and connect this to a number of developments in science and society. I conclude with four remarks on the future of the ethics of the Three Rs principle.