Cathepsin D (cath-D) overexpression in breast cancer cells is associated with increased risk of metastasis in patients according to several clinical studies. No alterations of pro-cath-D structure or activation have been demonstrated in cancer cells. However, overexpression and dysrouting of pro-cath-D in illegitimate compartments could have consequences on tumor progression. Transfection of a human cDNA cath-D expression vector increases the metastatic potential of 3Y1-Ad12 embryonic rat tumorigenic cells when intravenously injected into nude mice. The mechanism by which cath-D increases the incidence of clinical metastasis seems to involve increased cell growth and decreased contact inhibition rather than escape of cancer cells through the basement membrane. Different mechanisms are discussed by which cath-D could act as a protease following its activation or as a ligand of different membrane receptors at a more neutral pH.