Darwin’s explanation of biological speciation in terms of variation and natural selection has revolutionised biological thought. However, while his principle of natural selection, the fitness principle, has shaped biology until the present, its interpretation changed more than once during the almost 150 years of its history. The most striking change of the status of the principle is that, in the middle of the 20th century, it transmutated from an often disputed, groundbreaking insight into a tautology. Moreover, not only the interpretation of the fitness principle, but the whole body of biological knowledge was subjected to significant modifications. In this paper, I relate modifications of the fitness principle to those of the respective body of biological knowledge. This body of knowledge is conceived as a Quinean web of belief. After an exposition of Darwin’s conception of the principle, which equated fitness with adaptedness to the environment, several of its changes are analysed with respect to different webs of biological knowledge. It is concluded that the different interpretations and the reshaping of the fitness principle are rational responses to the modified systems of background knowledge, which saved the coherence of the web of biological knowledge in each single case.