Bladder cancer is a disease of older patients who often have multiple comorbidities. Although cisplatin-based combination chemotherapy is the standard of care in the neoadjuvant and metastatic settings, outcomes remain poor, and approximately half of patients are ineligible for cisplatin where treatment options are severely limited. Recent comprehensive genome sequencing studies have defined the mutational spectra of high-grade urothelial carcinoma of the bladder. Although there is a high prevalence of potentially actionable genomic alterations, whether these events represent true oncogenic vulnerabilities has yet to be confirmed. Given the demographics and genetics, we propose that bladder cancer represents an ideal model to study the potential of targeted therapy in older patients who are too often unable to receive cisplatin-based therapy and where novel treatment strategies are desperately needed.