A few years ago, it would have been difficult to argue that elucidating the mechanisms of disease resistance in the fruit fly, Drosophila melanogaster, would provide new insights into mammalian immunity. Yet the finding that the Drosophila protein Toll mediates immune responses to fungal infection had a pioneering role in the identification of Toll-like receptors as essential regulators of mammalian host defence, and it fundamentally altered our understanding of innate immunity. In this Landmark article, I describe the thought processes and the experimental steps that defined Toll as a key regulator of Drosophila immune responses.