While the presence of stromal fibroblasts within malignant tumors was established many decades ago, it is only recently that their role in tumorigenesis has begun to unravel. Probably the most important finding in this line of research is that, contrary to the conventional notion that views them as a static entity, stromal fibroblasts progress in parallel with the cancer cells, interacting continuously with them and affecting the kinetic profile and the morphology of the tumor. However, while the tumor is highly dependent on the stromal fibroblast during the early stages of disease development, it is likely that it abolishes this dependency at later stages. The aim of this article is to outline the evidence implying this differential dependency of the cancer cells against the stromal fibroblasts, and to discuss their implication in the management of the disease, especially in view of the evolving concept of stroma-targeting anticancer therapies.