During microbial infection, pre-existing memory CD8⁺ T cells that are not specific for the infecting pathogens can be activated by cytokines without cognate antigens, termed bystander activation. Studies in mouse models and human patients demonstrate bystander activation of memory CD8⁺ T cells, which exerts either protective or detrimental effects on the host, depending on the infection model or disease. Research has elucidated mechanisms underlying the bystander activation of CD8⁺ T cells in terms of the responsible cytokines and the effector mechanisms of bystander-activated CD8⁺ T cells. In this Review, we describe the history of research on bystander CD8⁺ T cell activation as well as evidence of bystander activation. We also discuss the mechanisms and immunopathological roles of bystander activation in various microbial infections.