Most febrile nonhemolytic transfusion reactions (FNHTR) to platelets are caused by cytokines that accumulate in the product during storage. There have been numerous studies that have demonstrated high concentrations of leukocyte- and platelet-derived cytokines in stored platelet products. The mechanism of cytokine accumulation is not understood; however, recent studies have suggested that leukocyte apoptosis and/or monocyte activation during the manufacturing process may play a role. Additional support of cytokines as a cause of FNHTR is provided by a recently published randomized controlled trial that shows that removal of the supernatant plasma from platelets before transfusion significantly lowers the frequency of reactions and eliminates most of the severe reactions associated with platelet transfusions. Although cytokines appear to play a major role in causing platelet reactions, there is little evidence to support their role in causing erythrocyte reactions. Hence, it appears that most febrile nonhemolytic transfusion reactions to erythrocytes are probably the result of an incompatibility between leukocytes in the erythrocyte product and antibodies in the recipient's plasma. Recent studies have confirmed that the concentrations of proinflammatory cytokines in a wide variety of stored erythrocyte products are low. Also, there is no clinical evidence to suggest that the small quantities of cytokines present in stored erythrocyte products contribute to acute reactions to these products when transfused.