Collagen triple helix repeat containing protein 1 (Cthrc1) is a gene product with novel biochemical activities, and its ability to reduce collagen deposition by inhibition of Smad2/3 activation could have major clinical applications in the fields of vascular disease, repair, and fibrosis. Currently available data indicate that Cthrc1 expression in vascular cells regulates transforming growth factor beta responsiveness, thereby impacting transforming growth factor beta target genes, including collagens; and regulation or activation of Cthrc1 is strictly controlled in these cells. Determining Cthrc1 activation (or inactivation) and addressing the interaction with known signaling pathways are important aspects aimed at developing this work toward clinically relevant applications.