The matrix metalloproteinase (MMP) family of extracellular proteinases have long been associated with cancer invasion and metastasis by virtue of their ability to collectively degrade all components of the extracellular matrix (ECM). The general belief that overexpression of a specific MMP, either by tumor cells or the surrounding stroma, is pro-tumorigenic led to the development of synthetic MMP inhibitors for the treatment of cancer. However, there is an increasing amount of literature demonstrating that the expression of certain MMPs, either at the primary or the metastatic site, provides a beneficial and protective effect in multiple stages of cancer progression. Here, we review the evidence for protective effects of MMPs and contrast this with pro-tumorigenic effects of either the same enzyme, or a different MMP of the same family. These studies highlight the importance of targeting specific MMPs for cancer treatment, and point to a potential reason why clinical trials of pharmaceutical inhibitors for MMPs were disappointing. In order to effectively target MMPs in cancer progression, a better understanding of both their pro- and anti-tumorigenic effects is required.