The paradigm for tumor-host interaction in the context of prostate to bone metastases is the “vicious cycle” in which PTHrP, RANKL and TGFβ play key roles. In animal models and human specimens, we have found that matrix metalloproteinases (MMPs) are highly expressed in the metastatic bone microenvironment. Although MMPs are implicated in extracellular matrix turnover, emerging results from our group define MMPs as principle mediators of vicious cycle via their ability to regulate bioactivity and bioavailability of factors such as PTHrP, RANKL and TGFβ. We have found that individual MMPs expressed in the bone microenvironment; 1) can process mature PTHrP into a number of distinct fragments that impact osteoblast cell signaling; 2) generate soluble RANKL that acts as a factor in the recruitment of osteoclast precursors and; 3) are critical for the generation of bioavailable TGFβ. We posit that the selective inhibition of MMPs by novel bone seeking MMP inhibitors or that targeting MMP substrate neo-epitopes can lead to the generation of therapies which will halt the vicious cycle and ultimately cure prostate to bone metastases