The modern era of systemic treatment of urological cancers is definitely marked by checkpoint inhibitors. Over the past 30 years, checkpoint inhibitors have changed the oncological world, especially in chemoresistant malignancies. Multiple investigations focused on immunotherapy in urological cancers have carved new paradigms and changed clinical guidelines. However, some clinical trials have been blind alleys for systemic therapy. After a scrutinized review of electronic databases, we want to present the natural history and courses of clinical trials in urological malignancies. All of them contribute to expanding the knowledge and experience of clinicians, and some of them improve the prognosis and prolong the overall survival of oncological patients. In conclusion, checkpoint inhibitors open a new modern era in some urological cancers, but not overall. Future perspectives are focused on combination with targeted therapy and could be a new way forward in the systemic treatment of urological cancers.