Since its introduction in the early 1980s, intravesical instillation of live bacillus Calmette-Guérin (BCG) remains the gold standard immunotherapeutic approach for eradication of carcinoma-in-situ of the bladder and for prevention of recurrence for patients with papillary high-risk non-muscle invasive bladder cancer (NMIBC). Despite the success of BCG, response is not uniform and limited options exist for unresponsive tumors. Currently, there is no combination therapy in use to enhance BCG’s activity. To address this unmet need, this article examined a novel approach to boosting BCG activity using low-dose rapamycin (Sirolimus).