In this theoretical paper, we explore the role that sign-making practices such as differentiation into parts and integration of parts play for successful student learning in science. Taking a social semiotic stance, we view student interest, such as their judgement of what is relevant and appropriate for the situation at hand and of who is the ‘reader’ of the sign, as the basis for their sign-making. Thus, sign making includes judgements of what to say, how to say it, and by what means to say it – viz. speech, writing, drawing, etc. Our explorative investigation is guided by a multimodal approach to sensemaking, and our analyses are illustrated with excerpts from classroom video data collected when first year upper secondary school students attempt to explain an experimental model of the greenhouse effect. The implications for teaching and learning include that in order to enhance student learning in science, learning tasks need to be created that engage students and prompt their sign-making. By supporting students in focusing on differentiation and integration of parts, students get the tools they need to develop their way of knowing. Thus teachers should pay close attention to students’ sign-making and how it can be supported.