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Advanced biliary tract cancers (BTCs) have historically been managed with chemotherapy but, in recent years, this treatment paradigm has begun to shift with the introduction of immune checkpoint inhibitors in addition to standard of care chemotherapy. The tumor microenvironment of BTC may be enriched with regulatory T lymphocytes and immune checkpoint expression in some patients. Durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, in combination with gemcitabine and cisplatin, has now received United States Food and Drug Administration approval for treatment of advanced BTC. Regulatory approval was based on the Phase III, randomized TOPAZ-1 trial that demonstrated survival benefit with addition of durvalumab to gemcitabine plus cisplatin compared to chemotherapy alone. The combination of chemotherapy and immunotherapy was well tolerated, and a subset of patients were able to achieve a durable response, with a 2-year overall survival rate of 23.6%. However, limitations remain in identifying which patients are most likely to benefit from immune checkpoint inhibition. Future study should aim to identify biomarkers predictive of substantial benefit, as well as the role of immune checkpoint inhibition in combination with targeted therapies and radiotherapy in the management of advanced BTC., Competing Interests: Zhaohui Jin reports advisory board for Novartis, QED therapeutics, Lilly, GlaxoSmithKlein, Daiichi Sankyo/Astra Zeneca, Exelixis, and Elevar Therapeutics. Amit Mahipal reports speakers bureau, advisory board for AstraZeneca; speakers bureau for Exelixis; advisory board for Taiho Oncology and Elevar Therapeutics; and research funding from Pfizer. The authors report no other conflicts of interest in this work., (© 2024 Storandt et al.)