Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression. Display omitted •BET inhibitors suppress PD-L1 expression in both immune cells and tumor cells•CD274 is a direct target gene of BRD4•BET inhibitors increase cytotoxic T cell activity to limit tumor progression in mice Zhu et al. find that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer in mice. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. Together, these data suggest a small-molecule approach to blocking PD-L1 signaling.