Indirect calorimetry (IC) is the gold standard for measuring resting energy expenditure (REE) in the critically ill patient. The use of predictive equations to develop nutrition regimens can be problematic in the critical care setting, because the effects that disease, injury, and stress have on REE are often varied and unpredictable. IC testing ensures that the specific conditions of the critically ill patient are taken into account, thereby preventing potential complications from over- and underfeeding. The clinical indications for and appropriate applications of IC testing are discussed. In addition, 3 case studies are presented that highlight the application of IC. The clinician can face numerous obstacles in implementing IC testing, including lack of equipment, staff shortages, and lack of knowledge regarding application and interpretation of the IC study. Recommendations for addressing these challenges are discussed. In addition, guidelines on ordering and interpreting the IC study are provided. Best practices for predictive equations in critically and acutely ill patients are also presented, since IC testing is not feasible in certain situations. Given the importance of predicting REE in the critically ill patient, it is paramount that more healthcare professionals incorporate IC testing into practice. A multidisciplinary approach is helpful in developing a well-established clinical practice. Nutrition support clinicians can promote optimal nutrition management by being well-informed and able to provide evidence-based recommendations for the use of IC.