To understand the organization of the biological networks that might potentially govern the pathogenesis of hormone refractory prostate cancer (HRPC), we investigated the transcriptional circuitry and signaling in androgen-dependent 22Rv1 and MDA PCa 2b cells, androgen- and estrogen-dependent LNCaP cells, and androgen-independent DU 145 and PC-3 prostate cancer (PCa) cell lines. We used microarray analyses, quantitative real-time PCR, pathway prediction analyses, and determination of Transcription Factor Binding Site (TFBS) signatures to dissect HRPC regulatory networks. We generated graphical representationsof global topology and local network motifs that might be important in prostate carcinogenesis. Many important putative biomarker ‘target hubs’ were identified in the current study including AP-1, NF-қB, EGFR, ERK1/2, JNK, p38 MAPK, TGF beta, VEGF, PDGF, CD44, Akt, PI3K, NOTCH1, CASP1, MMP2 and AR. Our results suggest that complex cellular events including autoregulation, feedback loops and cross-talk might govern progression from early lesion to clinically diagnosed PCa, as well as metastatic potential of pre-existent high-grade prostate intraepithelial neoplasia (HG-PIN) and/or advancement to HRPC. The identification of TFBS signatures for TCF/LEF, SOX9 and ELK1 in the regulatory elements suggests additional biomarkers for the potential development of chemopreventive/therapeutic strategies against PCa. Taken together, in this study, we have identified putative biomarker ‘target hubs’ in the architecture of PCa signaling networks, and investigated TFBS signatures that might enhance our understanding of key regulatory nodes in the progression and pathogenesis of HRPC.