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Prime time for immunotherapy in advanced urothelial cancer. BACKGROUND: Metastatic urothelial cancer (UC) is a lethal disease. Until 2016, cytotoxic chemotherapy with substantial toxicity was the only therapeutic option. In the first-line metastatic setting, cisplatin-based combination chemotherapy remains the standard of care. For cisplatin-ineligible patients, carboplatin-based regimens that are less efficacious are often substituted. In platinum-refractory patients, taxanes and vinflunine are the most commonly used. Recently, treatment options have largely expanded with the development of the immune checkpoint inhibitors (ICIs). Here, we review the rationale, clinical trial data and recent advances in biomarker development in the field of immuno-oncology in this disease site. We will also explore future directions of the field with respect to sequencing and combination strategies. METHODS: A comprehensive literature review was performed using Pubmed, clinicaltrials.gov, and conference proceedings from the European Society of Medical Oncology (ESMO) and the American Society of Oncology (ASCO). RESULTS AND CONCLUSION: ICIs have disease activity in metastatic UC. Five ICIs gained FDA regulatory approval in metastatic UC in patients with platinum-refractory disease. Of these five agents, pembrolizumab has level I evidence based on the KEYNOTE-045 phase III trial showing an overall survival benefit of 3 months over standard chemotherapy. ICIs also play a role in the first-line setting for patients who are cisplatin ineligible. Currently, ICIs are administered to unselected patients as reliable predictive biomarkers are lacking; however, this is a very active area of research. The rapid expansion of ICIs has also led to many upcoming trials, testing ICIs earlier in the disease course and in various combination strategies. Studies on optimal sequencing of therapies are eagerly awaited.