Interactions involving tumor cells and the extracellular matrix (ECM) strongly influence tumor development, including head and neck tumors, affecting cell proliferation and survival as well as the ability to migrate beyond the original location into other tissues to form metastases. These cell migration is often facilitated by partial destruction of the surrounding ECM, which is catalyzed by matrix metalloproteinases (MMPs), a family of more than 20 endopeptidases that is controlled by regulated expression of specific inhibitors (TIMPs). Several studies of ECM and MMPs markers have provided additional diagnostic and prognostic information in head and neck carcinomas. In this review, we are considering the role of ECM and MMPs in tumor progression, emphasizing its proteolytic contributors to this process, and interactions between several members of ECM providing substrate to regulation of this process.