Creative reasoning and problem-solving are crucial to how scientists work and how students learn in school science. However, developing guided inquiry that develops these capabilities within a prescriptive curriculum has proven difficult. In this paper, we report on a study of a teaching sequence that aimed to develop these capabilities through structured inquiry where students responded to representational challenges on the topic of respiration in senior secondary biology. We found that this activity engaged students and improved conceptual understanding. Students had many opportunities to practise reasoning skills in negotiating, integrating, refining, defending and translating their ideas across representations. Key conditions supporting this learning included (a) students having some prior relevant understandings that enabled them to engage with the demands of the challenge, and (b) effective teacher guidance of student sign-making.