Eradicating cancer cells without inflicting collateral damage is a major challenge in cancer therapy, which has prompted the development of a variety of targeted therapeutic approaches. Bacillus Calmette–Guerin therapy by intravesical administration was first documented in the 1970s and has since become an important treatment option for transitional-cell carcinoma in situ of the bladder. Contrary to tumor cells in the hypoxic core, those in the well-perfused, highly proliferative tumor rim are sensitive to the conventional cytotoxic therapies. Ionizing radiation is another form of cytotoxic therapy that is often used effectively in an adjuvant setting. Thus, combining Clostridium novyi-NT treatment with chemo- or radiation therapy could prove effective in eradicating the entire tumor. Nevertheless, toxicity associated with C. novyi-NT treatment has been routinely observed. Clinical signs of toxicity are often seen when mice bearing large tumors are treated with spores through the intravenous or intratumoral route, and the toxicity is always associated with robust germination.