Following platinum-based regimens becoming the reference standard of care, it has taken almost four decades to find a systemic treatment that improved overall survival in metastatic urothelial tumors. Single-agent immune checkpoint inhibitors have not only improved overall survival but also the quality of life of patients with metastatic urothelial tumors after failure of platinum-based regimens and as a maintenance therapy after four to six cycles of standard first-line chemotherapy. In addition, very promising data are emerging when single-agent immunotherapy is offered as adjuvant or neoadjuvant treatment for patients with muscle-invasive disease and also in the non-muscle-invasive setting. There is an extensive debate about the role of PD-L1 expression as a reliable biomarker to predict the activity of immune-based regimens. Furthermore, the lack of consensus concerning its utility means that there is a need for more and better tools to identify patients who are likely to benefit from these novel approaches. The field of urothelial tumors now additionally exploits novel antibody-drug conjugates and fibroblast growth factor-receptor inhibitors that are being tested in combination with immunotherapy. This added complexity contributes to an enormous increase in the challenges that will be faced shortly.