The attenuated anaerobic bacterium Clostridium novyi-NT (C. novyi-NT) is known for its ability to precisely germinate in and eradicate treatment-resistant hypoxic tumors in various experimental animal models and spontaneously occurring canine sarcomas. In this article, we review the therapeutic and toxicologic aspects of C.novyi-NT therapy, key challenges and limitations, and promising strategies to optimize its performance via recombinant DNA technology and immunotherapeutic approaches, to establish C.novyi-NT as an essential tool in cancer therapy.