Recent advances in tumor biology have identified the stroma as an important regulator of carcinogenesis and potentially a valuable therapeutic target. While however the fact that by targeting the stromal component of a tumor represents a potential therapeutic strategy has been established, the knowledge for specific regulators for such interactions remains poor. The latter is largely due to the fact that appropriate methodological approaches that permit the screening for such regulators are lacking. In the present review we will summarize some of the literature underlining the central role of stromal factors, and essentially that of the fibroblasts in tumorigenesis. Furthermore, we will review the experimental evidence that suggest that by interfering with tumor – stroma interactions may represent a therapeutic approach. Finally, based on various experimental evidence and theoretical considerations we will suggest a biological experimental system which might facilitate the screening of such regulators.