A primary objective for science education is to impart robust knowledge that has applicability to real-world problems. This article presents research investigating the relationship between adolescents' conceptual understanding of the biological basis of HIV and critical reasoning. Middle and high school students were interviewed about their understanding of HIV and were subsequently asked to evaluate scenarios that contained myths about HIV. On the basis of their responses to the interview questions, students' understanding of HIV was categorized into three models, "naive," "intermediate," and "advanced." The results indicate that knowledge mediated students' responses in specific ways. Students at different levels of HIV knowledge reasoned in qualitatively different ways about the myths. A significant relationship was found between students' understanding of HIV biology and the level of biological reasoning. We found that students who employed cellular-level biological reasoning were more likely to reject the myths than students who employed just system-level reasoning or nonspecific biological reasoning. The findings emphasize the importance of conceptual understanding in the critical evaluation of information that may serve as a basis for making decisions about HIV. We conclude with discussing the implications of the findings for science and health education.