The mission of the President’s Precision Medicine Initiative (PMI) is to enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward the development of individualized care. Building from the existing PMI Privacy and Trust Principles, this document offers security policy principles and a framework to guide decision-making by organizations conducting or participating in precision medicine activities. Recognizing that there is no “one size fits all” approach to managing data security, this document provides a broad framework for protecting participants’ data and resources in an appropriate and ethical manner that can be tailored to meet organization-specific requirements.