In 2011, the Association of American Universities (AAU) embarked on an ambitious effort to improve the instructional quality and effectiveness of undergraduate introductory Science, Technology, Engineering, and Mathematics (STEM) courses. The primary focus was on sustainable implementation of evidence-based methods of instruction in courses that reach the largest number of students. AAU acknowledged that institutions, known for their research accomplishments, were part of the problem and could be part of a solution. This article discusses the approach taken by AAU and identifies the cross-cutting implementation, dissemination, and institutionalization strategies from eight pilot projects and from a growing network of AAU research universities committed to improving undergraduate STEM teaching and learning. What AAU has learned from its Undergraduate STEM Education Initiative can help us understand the process of systemic institution-wide educational reform, with emphasis on change being at the department level.