Some risks have extremely high stakes. For example, a worldwide pandemic or asteroid impact could potentially kill more than a billion people. Comfortingly, scientific calculations often put very low probabilities on the occurrence of such catastrophes. In this paper, we argue that there are important new methodological problems which arise when assessing global catastrophic risks and we focus on a problem regarding probability estimation. When an expert provides a calculation of the probability of an outcome, they are really providing the probability of the outcome occurring, given that their argument is watertight. However, their argument may fail for a number of reasons such as a flaw in the underlying theory, a flaw in the modeling of the problem, or a mistake in the calculations. If the probability estimate given by an argument is dwarfed by the chance that the argument itself is flawed, then the estimate is suspect. We develop this idea formally, explaining how it differs from the related distinctions of model and parameter uncertainty. Using the risk estimates from the Large Hadron Collider as a test case, we show how serious the problem can be when it comes to catastrophic risks and how best to address it.