Ought we to take seriously large risks predicted by “exotic” or improbable theories? We routinely assess risks on the basis or either common sense, or some developed theoretical framework based on the best available scientific explanations. Recently, there has been a substantial increase of interest in the low-probability “failure modes” of well-established theories, which can involve global catastrophic risks. However, here I wish to discuss a partially antithetical situation: alternative, low-probability (“small”) scientific theories predicting catastrophic outcomes with large probability. I argue that there is an important methodological issue (determining what counts as the best available explanation in cases where the theories involved describe possibilities of extremely destructive global catastrophes), which has been neglected thus far. There is no simple answer to the correct method for dealing with high-probability high-stakes risks following from low-probability theories that still cannot be rejected outright, and much further work is required in this area. I further argue that cases like these are more numerous than usually assumed, for reasons including cognitive biases, sociological issues in science and the media image of science. If that is indeed so, it might lead to a greater weight of these cases in areas such as moral deliberation and policy making.