Matrix metalloproteinases (MMPs) play an important role in degradation of extracellular matrix (ECM), which is an essential step in the cascade of metastasis. Various types of MMPs are expressed and activated in head and neck squamous cell carcinoma (HNSCC) as well as other human cancers. MMP-2 is a prominent predictor of poor prognosis. Membrane type 1-MMP (MT1-MMP) was originally identified as an activator of MMP-2. In addition to the original role, recent studies show other important functions of MT1-MMP such as degradation of type I collagen and cleavage of CD44. Tissue inhibitor of MMP-2 (TIMP-2) was identified as an inhibitor of MMP-2 and MT1-MMP. However, TIMP-2 was reported to be essential for cell-mediated activation of MMP-2, and thus the contribution of TIMP-2 to tumor invasion has remained controversial. Some studies also suggested a role of TIMP-2 as a predictor of poor prognosis. Thus, inhibition of MMP activation by TIMPs is not a suitable strategy for suppressing invasion and metastasis. Instead of TIMP-2, various MMP inhibitors (MMPI) such as BB-2516 have been investigated with regard to suppression of tumor progression and improvement of prognosis in patients with advanced cancers, which resulted in no clinical efficacy. MMPs are especially important in the early stage of cancer progression, and thus strategies for future MMPI trials should be reconsidered.