Bacteria have been investigated as anti-tumor therapeutic agents for more than a century, since Coley first observed successful curing of a patient with inoperable cancer by injection of streptococcal organisms. Previous studies have demonstrated that some obligate or facultative anaerobes can selectively accumulate and proliferate within tumors and suppress their growth. Developments in molecular biology as well as the complete genome sequencing of many bacterial species have increased the applicability of bacterial organisms for cancer treatment. In particular, the facultative anaerobe Salmonella Typhimurium has been widely studied and genetically engineered to improve its tumor-targeting ability as well as to reduce bacterial virulence. Moreover, the effectiveness of engineered attenuated S. Typhimurium strains employed as live delivery vectors of various anti-tumor therapeutic agents or combined with other therapies has been evaluated in a large number of animal experiments. The well-known S. Typhimurium mutant VNP20009 and its derivative strain TAPET-CD have even been applied in human clinical trials. However, Salmonella-mediated cancer therapies have not achieved the expected success, except in animal experiments. Many problems remain to be solved to exploit more promising strategies for combatting cancer with Salmonella bacteria. Here, we summarize the promising studies regarding cancer therapy mediated by Salmonella bacteria and highlight the main mechanisms of Salmonella anti-tumor activities.