Tumor progression occurs within a microecosystem, where cancer cells and myofibroblasts exchange proteinases and cytokines that promote growth directly through stimulation of proliferation and survival, as well as invasion through local proteolysis of the extracellular matrix and stimulation of motility. Myofibroblasts maintain the capacity of fibroblasts to induce differentiation. Fibroblasts are the main source of tumor-associated myofibroblasts. The transition to myofibroblasts also occurs in noncancerous situations. This transition is modulated by mechanical stress and cytokines, amongst which transforming growth factor-beta. The cross-talk between cancer cells and myofibroblasts illustrates the microecosystem of tumor invasion. In order to consider myofibroblasts as a possibly new target for cancer therapy, further characterization of the molecular cross-talk between myofibroblasts and cancer cells is required.