The term conceptual simulation refers to a type of everyday reasoning strategy commonly called “what if” reasoning. It has been suggested in a number of contexts that this type of reasoning plays an important role in scientific discovery; however, little direct evidence exists to support this claim. This article proposes that conceptual simulation is likely to be used in situations of informational uncertainty, and may be used to help scientists resolve that uncertainty. We conducted two studies to investigate the relationship between conceptual simulation and informational uncertainty. Study 1 was an in vivo study of expert scientists; the results suggest that scientists do use conceptual simulation in situations of informational uncertainty, and that they use conceptual simulation to make inferences from their data using the analogical reasoning process of alignment by similarity detection. Study 2 experimentally manipulated experts' level of uncertainty and provides further support for the hypothesis that conceptual simulation is more likely to be used in situations of informational uncertainty. Finally, we discuss the relationship between conceptual simulation and other types of reasoning using qualitative mental models.