Significance CD8 T cell exhaustion is a key underlying factor limiting immunity in chronic infections and cancer. Persistent antigen exposure antagonizes formation of functional memory CD8 T cells that provide long-term protection and, instead, drives the development of exhausted CD8 T cells (T _EX ). Improving T _EX persistence and function is a major goal for reinvigorating immune responses against chronic infections and tumors. Here, we identify miR-29a as a molecule that attenuates exhaustion and enhances persistence and function of T _EX . Enforced expression of miR-29a alters T _EX transcriptome, resulting in robust changes in molecular pathways governed by fundamental transcription factors and epigenetic modulators. Thus, enforced miR-29a expression enhances T _EX responses, attenuates exhaustion, and represents a target for improving the outcome of immunotherapy.