Major opportunity exists to better align clinical science and clinical practice. To do so will require efforts not only to develop clinical practice guidelines, but to facilitate their application in practice. The American College of Cardiology operates a program to develop and assess the effectiveness of tools that facilitate the application of guidelines in practice. Here we review what we have learned about the process of guideline implementation, lay out the major research questions that need to be addressed, and argue that professional societies play a critical role in moving from guideline development to application.