In the upper aero-digestive tract mucosa, including the oral cavity, squamous cell carcinoma (SCC) represents 85-90% of malignant neoplasia.For decades there has been little improvement in patient prognosis, and 5-yr survival remains <60%, in part because existing treatment strategies do not take into account the influence of the microenvironment on cancer cell survival and disease progression.Currently, there is increasing appreciation of the important role the tumor microenvironment plays in cancer progression, and the regulatory mechanisms controlling the cancer microenvironment are under intense investigation.The SCC microenvironment is very complex and rich in immune system cells, bacteria, along with mesenchymal elements.Our research is focused on new approaches that scrutinize the interactions between SCC cells and the elements of the microenvironment, including inflammatory cells and microbial products.Besides functional analyses of SCC cell lines and specific inflammatory cells, we have been developing ex vivo studies of fresh mixed cell explants from SCC to preserve tumor cell-stromal cell influences.We are also advancing the organotypic culture model for the purpose of evaluating tumor cell-stromal cell influences in a three-dimensional system, including the effects on tumor cell survival and invasion.The advancement of these approaches will facilitate physiologically relevant testing of therapies that target both tumor cells and stromal elements.The presentation will provide an overview of the current understanding of the oral SCC microenvironment with recent advances in research strategies.