The metabolic changes associated with critical illness involve several pathways acting at different steps of the utilization of nutritive substrates. The understanding of the role of these pathways and of their complex regulation has led to the development of new strategies for the metabolic and nutritional management of critically ill patients, including the development of new products for nutritional support. The rationale for changing the profile of nutritional support solutions by adding novel substrates is also discussed. This review focuses on the metabolic specificities of critically ill patients and also includes an analysis of the adequacy of tools to monitor the metabolic status and the adequacy of the nutritional support.