Androgen-independent (AI) progression remains the main obstacle to improving the survival of patients with prostate cancer. Recently, we characterized changes in gene expression profile during AI progression in the prostate cancer model systems as well as the clinical specimens, and identified several genes, including bcl-2, bcl-xL, clusterin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-5 and heat shock protein 27, that are involved in the signal transduction pathways mediating resistance to various kinds of apoptotic stimuli. We then showed the efficacy of inactivating such antiapoptotic genes using antisense (AS) oligodeoxynucleotides (ODNs) to delay AI progression after androgen withdrawal. We further demonstrated the synergistic effects of AS ODN therapy combined with several treatments, such as cytotoxic chemotherapy, radiation and other molecular targeting therapies. In this review, we attempted to summarize the progress we have made in the field of AS ODN strategy against prostate cancer, and to discuss the preliminary data of the recently completed phase I clinical trials using AS ODNs as well as the future prospects of this therapy. The findings presented in this review may help clarify the significance of AS ODN therapy targeting relevant genes as an attractive alternative to conventional strategies for prostate cancer.