Several classes of extracellular matrix (ECM)-degrading proteases have been shown to play an important role in tumor invasion and metastasis. Among them, the matrix metalloproteinases (MMPs) and the plasminogen activator (PA)-plasmin system have been the focus of numerous studies. However, few of those have examined the interaction of these two classes of proteases during tumor progression and their specific roles in this complex process have remained unclear. In this article, comparative information on the structure, function, and regulation of these two classes of proteases is reviewed and their interaction on various levels is discussed. This review shows that MMPs and the PA-plasmin system closely cooperate to achieve optimal degradation of the ECM during the invasive and metastatic process.