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The Illinois Mathematics and Science Academy (IMSA), as a self-described “teaching and learning laboratory for imagination and inquiry,” has a history of pursuing innovations closely aligned with the vision and framework of the National Science Education Standards. Innovations include both methods and materials for inquiry-based student instruction as well as for delivering professional development for pre-service and practicing teachers. In addition to describing successful innovations, this chapter contains specific results and a constellation of evidence for each program, which serve to demonstrate the efficacy of IMSA’s efforts in four areas: (1) improving students’ deep conceptual understanding of critical STEM concepts; (2) promoting students’ advanced studies and pursuit of STEM careers, including becoming mathematics and science educators; (3) changing teacher practices; and (4) developing a culture in which students not only become advanced “power users” of scientific principles but retain a commitment to IMSA’s mission of “advancing the human condition” long after they leave school. The chapter concludes with recommendations for organizations and institutions seeking to replicate these and similar practices as well as advancing and scaling these practices through generative networks and pioneering technologies.