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