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Abstract All of medicine aspires to be precise, where a greater understanding of individual data will lead to personalized treatment and improved outcomes. Prompted by specific examples in oncology, the field of critical care may be tempted to envision that complex, acute syndromes could bend to a similar reductionist philosophy—where single mutations could identify and target our critically ill patients for treatment. However, precision medicine faces many challenges in critical care. These include confusion about terminology, uncertainty about how to divide patients into discrete groups, the challenges of multi-morbidity, scale, and the need for timely interventions. This review addresses these challenges and provides a translational roadmap spanning preclinical work to identify putative treatment targets, novel designs for clinical trials, and the integration of the electronic health record to implement precision critical care for all.