Advanced prostate and ovarian cancers metastasise to distinct anatomical locations. The former spreads predominantly to regions of the skeleton where haematopoiesis is occurring, and the later disseminates throughout the peritoneal cavity. While metastasis to these sites requires distinct molecular mechanisms, our data suggest that proteolysis of cell surface receptors is important in the advanced stages of both pathologies. In the case of prostate cancer, mouse model data indicate that a member of the protease activated receptor family of GPCRs mediates growth of prostate cancer bone lesions, potentially via activation of pro-inflammatory signalling pathways. Antagonism of this receptor appears to be effective at blocking tumor growth and limiting cancer-induced bone remodelling. In the case of ovarian cancer a different protease activated system, involving the cell surface receptor CDCP1, is important. In a subset of ovarian cancer patients proteolysis of CDCP1 appears to promote survival of malignant cells. Survival requires activation of intracellular signalling pathways, and our preliminary observations suggest that a portion of CDCP1, shed from the cell surface by proteolysis, may also be important. These observations will be discussed in the light of opportunities to disrupt advanced stage prostate and ovarian cancer by blockade of protease activated signalling.