Urothelial cell carcinoma (UC) is one of the most common cancers and one of the most deadly. Metastatic UC is particularly hard to treat, because it is typically diagnosed when patients are elderly and have medical comorbidities. Many patients with metastatic UC are unable to receive cisplatin-based chemotherapy, due to older age at diagnosis and comorbidities, and even when platinum chemotherapy can be administered, it has limited success in prolonging survival. Recently, improved understanding of molecular targets and immunologic characteristics of urothelial tumor cells has resulted in new therapeutic approaches that may help optimize first- and second-line therapy. The most exciting of these approaches is inhibition of cytotoxic T-lymphocyte–associated antigen 4 or programmed cell death protein 1. These so-called “immune checkpoint” proteins are negative regulators of T-cell immune function, and inhibiting these proteins results in increased activation of the immune response to tumors. Two checkpoint inhibitors, atezolizumab and nivolumab, are now approved by the Food and Drug Administration as second-line therapy for advanced UC, and a wealth of clinical trials of these and other agents are ongoing. This review shows how oncology clinicians can incorporate checkpoint inhibitors into the management of patients with locally advanced or metastatic UC. It also introduces other forms of immunotherapy that are being investigated in bladder cancer: antibody-drug conjugates, vaccines, adoptive immunotherapy, and recombinant Bacillus Calmette–Guérin.