A short review of the literature first confirms the clinical value of cathepsin D as a prognostic marker in breast cancer, when using well standardized assays. We then summarize results of studies, mostly performed in our laboratory, aimed at understanding the effect of cathepsin D overexpression on metastasis and the molecular mechanisms involved. Cathepsin D-cDNA transfection increases tumor cell proliferation in vitro and the metastatic potential of 3Y1-Ad12 embryonic rat tumorigenic cells when injected in vivo into nude mice. The mechanism by which cathepsin D increases the incidence of clinical metastasis involves increased cell growth and decreased contact inhibition rather than escape of cancer cells through the basement membrane. Different mechanisms are considered to explain this mitogenic activity. Cathepsin D could act as a protease following its activation at an acidic pH, or as a ligand of different membrane receptors at a more neutral pH. In this case cathepsin D can displace IGFII from the mannose-6-phosphate/IGFII receptor to the IGFI receptor or activate another membrane receptor to be identified. The nature of the mechanisms involved in vivo may depend on the micro environment of the tumor cells. These studies should guide in the development of new therapies aimed at inhibiting the deleterious effect of overexpressed cathepsin D.