The pathogenesis of urinary tract infection and mechanisms of the protective effect of Bacillus Calmette-Guerin (BCG) therapy for bladder cancer highlight the importance of studying the bladder as a unique mucosal surface. Innate responses to bacteria are reviewed, and although our collective knowledge remains incomplete, we discuss how adaptive immunity may be generated following bacterial challenge in the bladder microenvironment. Interestingly, the widely held belief that the bladder is sterile has been challenged recently, indicating the need for further study of the impact of commensal microorganisms on the immune response to uropathogen infection or intentional instillation of BCG. This review addresses the aspects of bladder biology that have been well explored and defines what still must be discovered about the immunobiology of this understudied organ.