Can novel 3D models help students develop a deeper understanding of core concepts in molecular biology? We adapted 3D molecular models, developed by scientists, for use in high school science classrooms. The models accurately represent the structural and functional properties of complex DNA and Virus molecules, and provide visual and haptic feedback about biomolecular properties that are often implicit in traditional models. We investigated: 1) Can we measure improvement on core concepts? 2) Do lessons with 3D models improve student outcomes on these measures? and 3) What factors mediate learning? Model use yielded measurable gains in conceptual knowledge and the greatest gains were related to how actively models were used during a lesson and the facilitative role adopted by the teachers.