This chapter presents a complete synopsis of all clostridial genetic engineering activities that have been pursued to date in the context of cancer as well as an insight into the relevant genetic tools underpinning the efforts. Tumor-selective bacterial colonization is guaranteed, given that the hypoxic and necrotic areas uniquely found in solid tumors are the only places in which spores can germinate and grow. The chapter discusses opportunities that could be pursued in the future, highlighting the great promise that clostridial delivery systems hold as a treatment for cancer. Improvement of the colonization efficiency and elimination of the outer rim have been the focus of ongoing efforts in the development of clostridial cancer therapy. Genetic engineering of clostridial strains in an effort to further enhance, fine-tune, and optimize their oncolytic properties seemed a reasonable step in the direction of clinically advancing the genus for cancer therapy.