The four endogenous tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. We have recently summarized the hierarchy of the relationships between TIMPs, metalloproteinases, their plethora of substrates, and the cellular processes that underlie cancer hallmarks. A number of powerful signaling pathways are also directly affected by this protease system. Strong trends of specific TIMP alterations have been noted in multiple human cancers, with TIMP1 overexpression and TIMP3 silencing individually associating with poor patient prognosis. To better understand the redundancy of TIMP function in tissue homeostasis and cancer biology, we have developed novel genetically engineered mouse models called as TIMPless mice. Data from these systems will be presented.