A critically ill polytrauma patient is one of the most complex cases to be admitted to the intensive care unit, due to both the primary traumatic complications and the secondary post-traumatic interactions. From a molecular, genetic, and epigenetic point of view, numerous biochemical interactions are responsible for the deterioration of the clinical status of a patient, and increased mortality rates. From a molecular viewpoint, microRNAs are one of the most complex macromolecular systems due to the numerous modular reactions and interactions that they are involved in. Regarding the expression and activity of microRNAs in sepsis, their usefulness has reached new levels of significance. MicroRNAs can be used both as an early biomarker for sepsis, and as a therapeutic target because of their ability to block the complex reactions involved in the initiation, maintenance, and augmentation of the clinical status.