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One of the most fundamental aspects of gene therapy for cancer continues to be targeting of therapeutic gene expression specifically to the tumor. In order to exclusively target malignant cells while at the same time sparing normal tissue, cancer gene therapy needs to combine highly selective gene delivery with highly specific gene expression. Specific bacterial strains have been considered as gene delivery vehicles as an alternative to viral vectors. We and others have been investigating the potential use of non-pathogenic anaerobic bacteria such as Clostridium. Their tumor specificity is based upon the unique physiology of solid tumors which is often characterized by regions of hypoxia and necrosis. We have constructed Clostridium strain that expresses the prodrug converting enzyme, nitroreductase that converts the prodrug CB1954 into a toxic agent that can kill dividing and non-dividing cells. As the enzyme is specifically targeted, high therapeutic doses are achieved only in the tumor. In vivo experiments using combined treatment of prodrug and recombinant bacteria administration resulted in a significant anti-tumoral response. Besides to Clostridium, the ability of the attenuated Salmonella to replicate preferentially in solid tumors demonstrated its potential use as gene delivery vector. However, despite its preferential tumor accumulation, normal tissues are also colonized albeit to a lesser extent. Although bacteria are cleared rapidly from the normal tissues, it negatively affects the specificity of the salmonella mediated gene transfer system. One way to address this problem is to obtain controlled gene expression when using attenuated Salmonella by exploiting tumor hypoxia. In that context, introducing a therapeutic gene under the transcriptional control of a hypoxia regulatory element might be promising.