Cystatins are natural cysteine protease inhibitors which belong to a superfamily of proteins with wide occurrence in tissues. The cystatins have been shown to play multiple roles in normal and disease processes. In many different cancers the cathepsins, enzymes inhibited by cystatins, are elevated and participate in tumor growth and invasion. The levels of the cystatins can vary quite widely in different cancers. Recent studies have shown cystatins can block invasion or metastasis of different cancers in experimental systems. Insights into cystatin roles in cancer have provided links to tumor development, angiogenesis, and tumor cell death in this devastating disease.