Patients with high-risk non-muscle invasive bladder cancer are treated with intravesical BCG immunotherapy, which facilitates removal of residual tumor cells after transurethral bladder tumor resection. However, BCG therapy has no effect in 30-50% of patients, while patients do experience BCGs toxic side effects. Moreover, the continuing worldwide BCG shortage demands we make selective use of limited resources. As of today, no adequate markers exist that may predict response to BCG therapy, so that patients that will not respond to BCG-therapy are timely identified, and perhaps offered a different treatment. Therefore, our team is investigating pathological, molecular and genomic markers that might be associated with response to BCG treatment. A more complete and fundamental understanding of BCG-treatment failure, innate and active immune system involvement, and factors related to drug resistance, might enable us to find alternative targeted therapies for patients with high-risk non-muscle invasive bladder cancer.