Eight articles addressed frameworks, and of these, the Joint Commission’s High Reliability Health Care Maturity Model (HRHCM) and the Institute for Healthcare Improvement’s (IHI) Framework for Safe, Reliable, and Effective Care emerged as the most comprehensive, rigorously developed, applicable, and sufficiently detailed to guide implementation. We identified 20 articles published on HRO frameworks, metrics, and evidence of effects. In this review, we evaluate literature on the frameworks for HRO implementation, metrics for evaluating a health system’s progress towards becoming an HRO, and effects of HRO implementation on process and patient safety outcomes. As literature has emerged to guide health systems in implementing and evaluating their HRO journey, an understanding of the quality and applicability of existing HRO resources is important to developing best practices, identifying barriers and facilitators to implementation, measuring progress, identifying knowledge gaps, and spreading implementation initiatives to other systems. In February 2019, the Department of Veterans Affairs (VA) rolled out a new initiative outlining the definitive steps toward becoming an HRO. Adoption of these HRO principles in health care offers promise of increased excellence however, major barriers to widespread implementation include difficulty in adopting organization-level safety culture principles into practice competing priorities between HRO and other large-scale organizational transformation initiatives such as electronic health records and difficulty in creating and implementing process improvement tools and methods to address complex, system-level problems. In 2008, the Agency for Healthcare Research and Quality (AHRQ) published a seminal white paper that described the application of the 5 key HRO principles in health care settings, including the specific challenges that threaten reliability in health care, such as higher workforce mobility and care of patients rather than machines. As death due to medical errors are estimated to be the third leading cause of death in the country, a growing number of health care systems are taking interest in adopting HRO principles. Nuclear power and aviation are classic examples of industries that have applied HRO principles to achieve minimal errors, despite highly hazardous and unpredictable conditions. High Reliability Organizations (HROs) are organizations that achieve safety, quality, and efficiency goals by employing 5 central principles: (1) sensitivity to operations ( ie, heightened awareness of the state of relevant systems and processes) (2) reluctance to simplify ( ie, the acceptance that work is complex, with the potential to fail in new and unexpected ways) (3) preoccupation with failure ( ie, to view near misses as opportunities to improve, rather than proof of success) (4) deference to expertise ( ie, to value insights from staff with the most pertinent safety knowledge over those with greater seniority) (5) and practicing resilience ( ie, to prioritize emergency training for many unlikely, but possible, system failures). However, the overall strength of evidence is low, as each HRO intervention was only supported by a single fair-quality study. Multicomponent HRO interventions delivered for at least years are associated with improved process outcomes ( eg, staff reporting of safety culture) and patient safety outcomes ( eg, serious safety events).