Bladder cancer is common and challenging to treat. A thorough assessment of the molecular biology and immunology background has pinpointed potential biomarkers, “drivers” and promising therapeutic targets. The advent of immune checkpoint inhibitors (ICI) has heralded a new era after approximately two decades of a “stagnant landscape”. As single agents in patients with advanced urothelial carcinoma, ICI can induce rapid and durable responses, with a very small proportion of patients achieving long term remission. However, most patients do not achieve response, while a proportion may have immune-related adverse events. Therefore, there is an urgent need for additional therapies that raise the bar, improve quality of life, and prolong the life of our patients.