When the history of the COVID-19 pandemic is written, it is likely to show thatthe mental models held by scientists sometimes facilitated their thinking,thereby leading to lives saved, and at other times constrained their thinking,thereby leading to lives lost. This paper explores some competing mentalmodels of how infectious diseases spread and shows how these modelsinfluenced the scientific process and the kinds of facts that were generated,legitimized and used to support policy. A central theme in the paper is therelative weight given by dominant scientific voices to probabilistic argumentsbased on experimental measurements versus mechanistic arguments based ontheory. Two examples are explored: the cholera epidemic in nineteenth cen-tury London—in which the story of John Snow and the Broad Street pumpis retold—and the unfolding of the COVID-19 pandemic in 2020 and early2021—in which the evidence-based medicine movement and its hierarchy ofevidence features prominently. In each case, it is shown that prevailingmental models—which were assumed by some to transcend theory butwere actually heavily theory-laden—powerfully shaped both science andpolicy, with fatal consequences for some.