The matrix metalloproteinases (MMPs) mediate homeostasis of the extracellular environment. They have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs. However, there are many criteria to consider in validating MMPs as drug targets and for the development of MMP inhibitors. The inhibition of some MMPs could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition. These effects might partially account for the failure of MMP inhibitors in clinical trials. What are the major challenges in MMP target validation and MMP-inhibitor-drug development?