Over the past 20 years, critical care has matured in a myriad of ways resulting in dramatically higher survival rates for our sickest patients. For millions of new survivors comes de novo suffering and disability called the Post-Intensive Care Syndrome (PICS). Patients with PICS are robbed of their normal cognitive, emotional, and physical capacity and cannot resume their previous life. The ICU Liberation Collaborative is a real-world quality improvement (QI) initiative being implemented across 76 ICUs designed to engage strategically the ABCDEF bundle through team- and evidence-based care. This article explains the science and philosophy of liberating ICU patients and families from harm that is both inherent to critical illness and iatrogenic. ICU Liberation is an extensive program designed to facilitate implementation of the Pain, Agitation, and Delirium (PAD) guidelines, using the evidence-based ABCDEF Bundle. Participating ICU teams adapt data from hundreds of peer-reviewed studies to operationalize a systematic and reliable methodology that shifts ICU culture from the harmful inertia of sedation and restraints to an animated ICU filled with patients who are awake, cognitively engaged, and mobile with family members engaged as partners with the ICU team at the bedside. In so doing, patients are liberated from iatrogenic aspects of care that threaten her or his sense of self-worth and human dignity. The goal of this 2017 plenary lecture at the 47th SCCM Congress is to provide clinical ICU teams a synthesis of the literature that led to the creation of ICU Liberation philosophy and to explain how this patient- and family-centered, QI program is novel, generalizable, and practice-changing.