Mesenchymal-epithelial interaction is important in the morphogenesis of squamous epithelia and their appendages, and in the control of the hair cycle postnatally. This review summarizes data regarding the interaction between stromal fibroblasts and tumor cells, with an emphasis on tumors originating from squamous epithelium. Tumor stromal fibroblasts as important element of the cancer stem cell niche are able to participate in the control of the biological properties of tumors. We propose these stromal cells and their products as novel targets for anticancer therapy.