The study of mechanisms by which drugs can modify cellular and ultimately whole animal and human performance is still one of the most exciting branches of science. However and despite the fact that many physicians are frequently using some times more than 20 drugs simultaneously in critically ill patients, very few of them are able to understand the enormous complexity and variability of different therapeutic responses within patients and/or between patients suffering from critical illness. The way in which most drugs behave in seriously ill subjects cannot be reliable predicted. Except for different distribution and elimination of various therapeutic regimens, altered pathophysiology, genetic predisposition and alterations in the number and/or intrinsic activity of different receptors may have an impact upon therapeutic effect through a myriad of mechanisms, leading to either under-resuscitation or intoxication of the patient. In this review, we will try to discuss basic pharmacodynamic (PD) principles and their association with severity of disease, trying at the same time to illustrate possible efficacy that can arise from their application during antibiotic treatment.