Gene therapy is a promising strategy to treat various inherited and acquired diseases. However, targeting gene expression to specific tissue is required to minimize side effects of gene therapy. Hypoxia is present in the microenvironment of solid tumors such as breast tumors. A hypoxic tumor targeting gene expression system has been developed for cancer gene therapy. In hypoxic tissues, hypoxia inducible factor (HIF)-1alpha is accumulated and stimulates transcription of the genes that have hypoxia response elements (HREs) in their promoters. Therefore, transcriptional regulation with a hypoxia inducible promoter is the most widely used strategy for hypoxic tumors targeting gene therapy. In breast cancer gene therapy, breast tumor specific promoters in combination with HREs have been used to induce gene expression in hypoxic breast tumors. Post-transcriptional regulation using an untranslated region (UTR) is also a useful strategy to increase gene expression in hypoxic tumor tissue. In addition, post-translational regulation with the oxygen-dependent degradation (ODD) domain is effective to eliminate therapeutic gene products and reduce side effects in normal tissue. In combination with the breast tumor specific promoters, hypoxic tumor targeting strategies will be useful for the development of a safe breast cancer gene therapy.