In prostate cancer metastases to bone, cancer cell-derived cytokines stimulate RANKL expression by cells of the osteoblast lineage, which in turn activates osteoclastic bone resorption. However, it is unclear whether cells of the osteoblast lineage signal back to prostate cancer cells, and if so, whether such direct cross-talk can be targeted therapeutically. Using the human prostate cancer cell line, PC3, we identified two novel signalling pathways acting between cells of the osteoblast lineage and cancer cells. First, exposure to RANKL stimulated the expression and release of IL-6 by PC3 cells in vitro (which is known to promote RANKL expression by osteoblasts). Second, treatment of PC3 cells with IL-6 increased the expression of RANK, the cognate receptor of RANKL, and enhanced the RANKL-induced release of IL-6 by PC3 cells. Third, targeted disruption of IL-6 signaling with tocilizumab, a clinically available antibody against the human IL-6 receptor, inhibited skeletal tumor growth in vivo and reduced serum RANKL levels as well as RANK expression by PC3-derived bone tumors. Similar effects were achieved when RANK expression was knocked down in PC3 cells. In contrast, disruption of IL-6 or RANK/RANKL signalling had no effect on PC3 tumor growth in soft tissues, indicating that these signalling pathways act specifically within the bone microenvironment. In conclusion, prostate cancer cells and cells of the osteoblast lineage communicate via two inter-dependent signaling pathways, which through auto-amplification strongly enhance metastatic prostate cancer growth in bone. Both pathways may be targeted for effective therapeutic intervention.