Vascular dissemination of cancer requires a series of cellular events including extravasation, the egress of cells across an endothelial cell layer. We have recently shown that a cell surface glycoprotein called CDCP1, that is upregulated in kidney, lung and pancreatic cancers, promotes this process (1). Our data indicate that CDCP1 is proteolytically processed at the cell surface in vitro (2) and in vivo (3) by serine proteases thereby initiating an intracellular signalling cascade involving activation and docking to CDCP1 of the kinases Src and PKCδ and downstream activation of Akt. Interestingly, we have shown that this cascade protects cancer cells as they extravasate in vivo and we have identified the protease essential for initiating this protection in a mouse model of metastasis (3). Our findings further demonstrate roles for CDCP1 in cell migration in vitro including its competition as a Src substrate with a critical mediator of cell adhesion FAK and its role in migration induced by EGFR signalling (4, 5). We speculate that targeting CDCP1 or CDCP1-induced signalling may be a rational approach to treat cancer patients at risk of recurrent disease.