The most obvious feature of expertise in chemistry is content knowledge, which defines the primary objectives of instruction. Research in chemistry education, and STEM education more broadly, has also devoted attention to students’ developing scientific practices of reasoning, investigation, and learning. In this study, we set out to investigate how expert chemists reason about an unfamiliar question. We conducted semi-structured, think-aloud interviews with fourteen chemists, all of whom found the problem novel. In this article, we focus on how the chemists handled the situation of not-knowing. We analyzed the moments when they said “I don’t know” (IDK), taking that as a clear, systematic marker of their not-knowing. The results elucidate two general dimensions of the chemists’ reasoning and experience. First, their identifying what they do not know served substantive roles in their reasoning, including to mark that they needed to search for insight or information, or to mark a boundary to the problem space. Second, IDK statements served to help the chemists manage what they experienced socially and emotionally, such as to hedge or distance themselves from ideas they considered, or to forestall their own—or the interviewer's—negative judgments. We discuss both aspects of our findings, and we consider possible implications for instruction and for further research.