Sepsis is the leading cause of death in most intensive care units, and the death of septic patients usually does not result from the initial septic event but rather from subsequent nosocomial infections. Patients who survive severe sepsis often display severely compromised immune function. Not only is there significant apoptosis of lymphoid and myeloid cells that depletes critical components of the immune system during sepsis, there is also decreased function of the remaining immune cells. Studies of animals and humans suggest the immune defects that occur during sepsis may be critical to pathogenesis and subsequent mortality. This review focuses on sepsis-induced alterations with the cluster differentiation (CD) 8 T-cell compartment that can affect the control of secondary heterologous infections. Understanding how a septic event directly influences CD8 T-cell populations through apoptotic death and homeostatic proliferation and indirectly by immune-mediated suppression will provide valuable starting points for developing new treatment options.