Both science and religion offer explanations for everyday events, but they differ with respect to their tolerance for mysteries. In the present research, we investigate laypeople's perceptions about the extent to which religious and scientific questions demand an explanation and the extent to which an appeal to mystery can satisfy that demand. In Study 1, we document a large domain difference between science and religion: scientific questions are judged to be more in need of explanation and less appropriately answered by appeal to mystery than religious questions. In Study 2, we demonstrate that these differences are not driven by differing levels of belief in the content of these domains. While the source of these domain differences remains unclear, we propose several hypotheses in the General Discussion.