Recent studies have begun to define the role of micro-RNAs in regulating the immune response. Micro-RNA155 (mir-155) has been shown to play a role in germinal center formation, T cell inflammation, and regulatory T cell development. In this study, we evaluated the role of mir-155 in cytotoxic T cell function. We report in this study that mice lacking mir-155 have impaired CD8(+) T cell responses to infections with lymphocytic choriomeningitis virus and the intracellular bacteria Listeria monocytogenes. We show by a series of adoptive transfer studies that the impaired CD8(+) T cell response to L. monocytogenes is T cell intrinsic. In addition, we observed that CD8(+) T cells lacking mir-155 have impaired activation of the prosurvival Akt pathway after TCR cross-linking. These data suggest that mir-155 may be a good target for therapies aimed at modulating immune responses.