Androgens and their cognate, the androgen receptor (AR), play a critical role in the development and progression of prostate cancer. In prostate cancer cells, after androgen binding, the AR is activated and dimerized, followed by nuclear translocation to regulate gene expression as a transcriptional factor. During this process, G-protein/PI3K-related events are involved at the plasma membrane and at the nuclear compartment. AR activation increases gene expression of major survival proteins to facilitate cellular survival. These downstream targets include cyclin-dependent kinase inhibitor p21waf1/cip1, forkhead transcription factor (FOXO1), cellular FLICE-like inhibitory protein (c-FLIP), serum/glucocorticoid-induced protein kinase 1 (SGK1), and anti-apoptosis member of Bcl-2 family protein Bcl-xL. Targeting the AR with gene-specific small interfering RNA (siRNA) in the AR-native prostate cancer cells induces massive responses of apoptotic cell death in the cultured cells in vitro and in the xenograft tumor models in vivo, demonstrating that the AR siRNA approach is feasible for clinical use in prostate cancer management. © 2013 Nova Science Publishers, Inc. All rights reserved.