Bromodomain-containing protein 4 (BRD4), a core component of the BET family, makes a contribution to transcriptional regulation and the genesis and progression of cancer. Through combining to acetylated histones, BRD4 promotes the transcription of oncogenes, drives cell cycle progression, enhances DNA damage repair, fosters tumor immunosuppression via PD-L1 upregulation, and supports telomere maintenance. Although early BRD4-targeted therapies, such as the classic inhibitor (+)-JQ1, demonstrated significant antitumor activity in preclinical studies, their clinical translation has faced numerous challenges. The purpose of this review is to summary the major mechanisms of tumor resistance in BRD4-targeted therapies, including the regulation of BRD4 protein stability, alterations in its phosphorylation state, and the activation of alternative signaling pathways. Building on this, we discuss dual-target inhibitors as a promising therapeutic strategy. By simultaneously targeting BRD4 and other oncogenic pathways or epigenetic regulators, these inhibitors aim to maximize therapeutic efficacy while reducing the likelihood of resistance. These approaches, which leverage synthetic lethality, epigenetic regulation, and cell cycle disruption, offer more effective anticancer outcomes. In the future, the optimization and clinical translation of BRD4 dual-target therapies are expected to provide significant breakthroughs in achieving precise and efficient cancer treatments.Copyright © 2025 Elsevier Inc. All rights reserved.