Disclosed are Cystatin C (CysC) homologues, including CystC homologues that act as antagonists or inhibitors of transforming growth factor-.beta. (TGF-.beta.). Also disclosed are methods to identify CystC homologues that are antagonists or inhibitors of TGF-.beta. and compositions and therapeutic methods using CystC and homologues thereof to regulate the activity of TGF-.beta., and TGF-.beta.-mediated tumor malignancy and invasion and other TGF-.beta.-mediated fibrotic or proliferative conditions and diseases.