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Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols. [Display omitted] • mSWI/SNF targeting and activity is specific to T cell activation and exhaustion states • Genetic and chemical disruption of cBAF complexes enhances T cell persistence • cBAF complex activities facilitate T cell exhaustion and prevent memory features • mSWI/SNF pharmacologic disruption improves CAR-T expansion and anti-tumor control mSWI/SNF ATP-dependent chromatin remodeling complexes direct chromatin accessibility and gene expression during T cell activation and exhaustion. Targeting mSWI/SNF complexes with clinically relevant small-molecule inhibitors and degraders attenuates T cell exhaustion and increases T cell persistence and anti-tumor activity in cell culture systems and in vivo. [ABSTRACT FROM AUTHOR]