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High reliability in healthcare is an elusive yet crucial concept to ensure meaningful, large-scale safety and quality improvement. Other industries such as nuclear power, aircraft carrier flight operations, and amusement parks have complex activities and operate in an environment with inherent hazards. In the case of these operations, failures are substantially lower as compared to what has historically been experienced in healthcare. This chapter explores the foundational characteristics of high reliability organizations and expounds upon real-world examples. Specifically, the Michigan Health & Hospital Association Keystone Center embarked on a 3-year quest with 90 of its member hospitals to infuse the principles of high reliability into every aspect of the organization. Results showed higher levels of staff engagement in hospitals with staunch leadership support, and some observed reductions in falls, Central Line Associated Blood Stream Infections and Catheter Associated Urinary Tract Infections. The experience of a large academic medical center is also described in detail, primarily focusing on the importance of patient and family engagement. This hospital utilized patient and family stories to highlight opportunities to advance the safety and quality of care, which in turn helped to successfully educate staff on the importance of becoming highly reliable.