Patients diagnosed with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) are treated with intravesical Bacillus Calmette-Guérin (BCG) instillations. While BCG treatment achieves a favorable outcome in roughly 50% of patients. Patients with BCG-resistant tumors require a complete removal of the bladder, a morbid procedure associated with a decreased quality of life. Furthermore, nearly half of the BCG-resistant tumors progress to muscle-invasive disease, resulting in a poor clinical outcome. Therefore, development of alternative treatment strategies for BCG-resistant tumors that will progress to muscle-invasive disease is crucial. Effectiveness of BCG largely depends on the molecular characteristics of the tumor. To investigate the effectiveness further, we have analyzed and compared the molecular profiles of tumors that respond differentially to BCG. Through this analysis, we identified key molecular differences that drive BCG-resistance and progression. Next, we have identified drugs that specifically target the molecular alterations responsible for BCG-resistance and progression. Because the tumors with these molecular alterations are BCG-unresponsive, these drugs hold potential as effective bladder sparing alternative treatments. We are currently investigating efficacy of these drugs ex vivo using our patient-derived bladder organoid culture system. Since bladder cancer organoids closely mimic the patients’ response to treatment, findings from this research can rapidly be translated into the clinic. Our work marks the initial progress towards personalized treatment for patients that currently have the worst clinical outcome.