As a result of a collaboration between the National Academy of Medicine (NAM) and the Office of the National Coordinator for Health Information Technology, this NAM Special Publication summarizes and builds on a meeting series in which a multi-stakeholder group of experts discussed the potential of clinical decision support (CDS) to transform care delivery by ameliorating the burden that expanding clinical knowledge and care and choice complexity place on the finite time and attention of clinicians, patients, and members of the care team. This summary also includes highlights from discussions to address the barriers to realizing the full benefits of CDS-facilitated value improvement. Optimizing Strategies for Clinical Decision Support identifies the need for a continuously learning health system driven by the seamless and rapid generation, processing, and practical application of the best available evidence for clinical decision making and lays out a series of actionable collaborative next steps to optimize strategies for adoption and use of CDS.