The discovery and targeting of genes mediating androgen-independence may lead to the development of novel therapies that delay progression of hormone refractory prostate cancer (HRPC). Clusterin is a stress-associated cell survival gene that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the use of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer models. Immunostaining of tissue microarrays constructed from untreated and post-hormone treated radical prostatectomy specimens confirm that clusterin is highly expressed in virtually all HRPC cells, 80% of prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Overexpression of clusterin in LNCaP cells confers resistance to both androgen ablation and chemotherapy. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels, accelerated apoptotic tumor regression, and significantly delayed the recurrence of androgen-independent tumors. A human clusterin ASO targeting the translation initiation site and incorporating MOE-gapmer backbone (OGX-011) synergistically enhanced the cytotoxic effects of paclitaxel in human xenografts of prostate, renal cell, bladder, and lung cancer. Clusterin, is an anti-apoptosis protein upregulated in an adaptive cell survival manner by androgen ablation and chemotherapy that confers resistance to various cell death triggers. Suppression of clusterin levels using ASOs enhances cell death following treatment with androgen ablation, radiation, and chemotherapy.