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Progress in the management of non-muscle invasive bladder cancer has been slow. Despite longstanding use of intravesical therapies (e.g., Bacille Calmette-Guerin; BCG) to complement cystoscopic resection of high-grade lesions, many patients still develop recurrences requiring cystectomy, while others suffer side-effects of BCG without definite benefit. Many questions remain: for example, how many patients receive intravesical prophylaxis without efficacy? Which high-risk patients are best managed with early cystectomy? Could systemic therapies and/or radiotherapy extend bladder preservation times? Such questions may soon be refined by clinicopathologic non-muscle invasive bladder cancer signatures that predict sensitivity to cytotoxic, immune and targeted therapies. Hypothesis-based trials using these signatures should lead to more rational adjuvant treatments, longer bladder preservation times, and better quality of life for patients.