Metalloproteinases are present across all kingdoms of living organisms and have expanded widely during eukaryotic evolution. They comprise the largest protease family in humans, and the metzincin clan in particular includes powerful secreted and cell surface-bound proteases. Metalloproteinase activity is naturally inhibited by the 4 TIMP proteins in mouse and human. The TIMP-metalloproteinase axis operates in every organ in the body and its disturbance is implicated in all human cancers and pathologies, yet the full spectrum of biology impacted by these proteases is not fully appreciated. This is in part related to the redundant functions of TIMPs as each TIMP can inhibit several metalloproteinases, with each protease overseeing numerous substrates. We are now able to uncover new biology by generating combinatorial TIMP knockouts, as well as models that are completely devoid of TIMP proteins. These quadruple deficient systems are opening new avenues towards understanding role of proteases in mammalian biology. The generation of these innovative systems as well as the newly discovered fundamental metalloproteinase biology will be discussed.