CD8 T cells comprise a powerful branch of the adaptive immune system, yet were not formally recognized until long after the discovery of antibody. CD8 T cells contribute to the eradication of intracellular infections and to the control of many chronic infections. There is tempered optimism that CD8 T cell memory elicited via vaccination may hold the key to manufacturing protective immunity against pathogens that cause chronic infections in humans. The specificity and destructive capabilities of CD8 T cells may also be harnessed for the eradication of tumors. However, CD8 T cells also contribute to a variety of clinical difficulties such as immune mediated pathology, rejection of organ transplants, and autoimmunity. Clearly, learning how to safely generate protective long-lived CD8 T cell memory and how to control or eliminate specific unwanted responses could deliver substantial clinical rewards, and there is a great need for continued research on the biology and therapeutic potential of these cells. Herein, we recount the historical developments leading to the discovery of CD8 T cells, highlight a few of the important discoveries that have followed, and discuss some of the critical issues on the horizon.