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The care of critically ill patients and the advent of the modern day intensive care unit (ICU) present a large person power and cost burden to society. The high cost of critical care is attributed to high overhead expenses (eg, experienced staff and equipment), high resource utilization (eg, pharmaceutical resources, lab testing, imaging procedures), and high demand for services. Pathways to standardize numerous facets of patient care have been shown to improve the efficiency of delivery of care and to reduce resource utilization, and are becoming the most sought-after means of improving patient outcomes and reducing overall ICU expenditures. A number of large, randomized, prospective trials have demonstrated that protocol-based strategies can not only reduce variation and cost of ICU medicine but also improve morbidity and mortality of critically ill patients requiring ICU support. In this article, we discuss examples of these trials investigating four major areas of modern ICU medicine: ventilator management, ventilator weaning, sedation and analgesia, and blood transfusions.