Proteases and kinases are involved in tumor progression. Regulation of signaling pathways by kinases is reversible, whereas switches catalyzed by proteases are irreversible. Regulatory networks of proteases and kinases are interconnected in multiple ways and inhibition of kinases and proteases provides a broad spectrum of approaches for cancer therapy. We addressed the role of lysosomal cysteine proteases in cancer progression and were able to show, that absence of cathepsin L (Ctsl) enhances tumor growth and invasion in the K14-HPV16 mouse model of squamous cell carcinoma. In contrast absence of cathepsin B (Ctsb) as well as Ctsb and cathepsin Z (Ctsz) reduces the tumor burden in the MMTV-PyMT mouse model of breast cancer. Cathepsins in tumors can be provided by cancer cells as well as by cells of the tumor microenvironment, e.g. cathepsins from tumor associated macrophages (TAMs) contribute to cancer progression. Analyses of the secretome of PyMT cancer cell and TAM cocultures revealed an elevated abundance of the cellular repressor of E1A-stimulated genes 1 (CREG1) in cocultures of PyMT cancer cells with Ctsb and Ctsz deficient TAMs in comparison to wild type controls. CREG1 inhibits cell proliferation and promotes cellular differentiation. Upon treatment of breast cancer cells with recombinant CREG1, a significant reduction in proliferation, migration and invasion has been observed. Furthermore, in MMTV-PyMT mice overexpressing Ctsb a reduced CREG1 level has been detected in the mammary cancer tissue interstitial fluid. In summary, we have shown that cysteine cathepsins are involved in the regulation of tumor progression and that CREG1, a putative substrate of cysteine cathepsins, has anti-tumorigenic properties. Because of its increased expression in cells and tumors from mice deficient for both Ctsb and Ctsz, this protein could provide a molecular mechanism explaining why mice lacking Ctsb and Ctsz have a reduced tumor burden.