This study used a cluster randomized controlled trial to investigate the effectiveness of two approaches to increasing middle school students' science learning when using an inquiry-based science curriculum. Eighty-nine schools, with 253 teachers and 20,591 students, were randomly assigned into one of three conditions: (a) a treatment condition in which the textbook curriculum was modified based on three principles of cognitive science coupled with teacher professional development (PD), (b) a second treatment condition in which teachers received PD designed to improve their knowledge of the science content, and (c) a business-as-usual control group. The cognitive science treatment had a small but statistically significant positive effect on content learning, with a stronger impact on students of higher prior achievement. Compared to business-as-usual, the intervention to increase teacher content knowledge had no impact.