Sepsis is a major cause of patient morbidity and mortality. Many critically ill patients are septic, and red blood cell transfusion is often part of their treatment plan. Studies have shown that red blood cell transfusion is associated with a dose-dependent increase in patient morbidity and mortality. Although red blood cells are transfused to increase the recipient's oxygen-carrying capacity, there are new and emerging data to support that red blood cell transfusion may potentially decrease perfusion and oxygen delivery to the microcirculation, particularly when older red blood cells are transfused. In addition, there are similar effects in the pathophysiology of sepsis that may overlap with the changes that occur with storage of red blood cells. This article will discuss recent literature addressing red cell transfusion in critically ill and septic patients and discuss general guidelines for red cell transfusion in this patient population. This article will also discuss the epidemiology and pathophysiology of sepsis and relate how storage and transfusion of red cells may potentially contribute to changes observed in a septic patient.