Despite significant progress in the development of new drugs and radiation, deaths due to cancer remain high. Many novel therapies are in clinical trials and offer better solutions, but more innovative approaches are needed to eradicate the various subpopulations that exist in solid tumors. Since 1997, the use of bacteria for cancer therapy has gained increased attention. Salmonella Typhimurium strains have been shown to have a remarkably high affinity for tumor cells. The use of bacterial strains to target tumors is a relatively new research method that has not yet reached the point of clinical success. The first step in assessing the effectiveness of bacterial tumor therapy will require strain development and preclinical comparisons of candidate strains, which is the focus of this chapter. Several investigators have developed strains of Salmonella with reduced toxicity and capacity to deliver anti-tumor agents. Although methods for obtaining safe therapeutic strains have been relatively successful, there is still need for further genetic engineering before successful clinical use in human patients. As described by Forbes et al. in 2003, the main stumbling block is that, while bacteria preferentially embed within tumor cells, they fail to spread within the tumor and finish the eradication process. Further engineering might focus on creating Salmonella that remove motility limitations, including increased affinity toward tumor-generated chemotactic attractants and induction of matrix-degrading enzymes.