Gene therapy using Salmonella has several possible advantages compared with other gene therapeutic tools, and Salmonella can be engineered according to the specific requirements of effective cancer therapy. As a delivery vector, Salmonella has been applied to gene therapy via three delivery routes: (1) the direct transfer of genes, (2) the delivery of proteins expressed by Salmonella, and (3) the transfer of plasmids encoding small hairpin RNAs. Usually, the therapeutic effect of Salmonella against cancer can be achieved according to several mechanisms of action, including prodrug-converting enzymes, cytotoxic agents, and immune response through these delivery routes. Salmonella can be engineered for the purpose of precise control of gene expression to maximize the intratumoral effects while minimizing the systemic toxicity and production of imaging signal to monitor therapeutic effects. Salmonella is expected to be a powerful tool that could replace or compensate for conventional cancer therapies through genetic engineering for “smart” bacteria.