The immune system remains an enigmatic system in that each discovery leads to more questions and speculation. It is essential for the critical care nurse to understand the basic physiology that occurs in infections to address the issues in patients in an efficient and timely manner. Thorough patient assessment helps determine predictors and priorities. Although the protective barrier of an intact integument system often is identified as the first and best line of defense against infections, this defense can be strengthened by a critical care nurse who is equipped with the knowledge and understanding of the immune system, the latest research, and the dynamics that ensue within the patient.