Epithelial-mesenchymal transition (EMT) in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor β1 (TGFβ1) and transcription factors including Snail and Slug. We utilized the ARCaP E/ARCaPM prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaPE cells, the highly tumorigenic mesenchymal ARCaPM and ARCaPM1 variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaPM and ARCaPM1 expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-βB Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGFβ1 treatment and Snail overexpression induced EMT in ARCaPE and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis. © 2008 IBCB, SIBS, CAS All rights reserved.