This chapter summarizes the developments in Salmonella-mediated cancer therapy and highlight the challenges that lie ahead. With rapid developments in the genetic modification of Salmonella, more and more researchers began to study Salmonella factors affecting tumor colonization and anticancer capacity. Salmonella pathogenicity island-2 was the first identified genetic system required for the anticancer capacity of Salmonella. R. W. Kasinskas and N. S. Forbes changed bacterial localization within tumors by deleting specific receptors in Salmonella, thereby improving the anticancer capacity of Salmonella. Bacteria-mediated cancer therapy is an emerging concept as it possesses some unique properties that make it unachievable through traditional methods. For bacterial delivery of cytotoxic compounds, genetic stability and a controllable high expression of heterologous genes are critical to ensure long-term release of therapeutic proteins. Avogadri and colleagues demonstrated that Salmonella-based therapy coupled with low-dose radiotherapy enhanced the anticancer capacity of Salmonella by dampening tumor immune escape mechanisms.