The microenvironment in which cancer arises plays a critical role in tumorigenesis. Although previously regarded as an innocent bystander, evidence has accumulated over the past 10 years that the microenvironment contributes to tumor growth and progression by providing nutrients and survival signals, and protecting the tumor from normal immune responses and anticancer drugs. Exactly how normal stromal cells, whose function should be to suppress malignant growth, become co-opted into facilitating tumor development is only just beginning to be understood, but a complex story is emerging wherein tumor and stromal cells appear to co-evolve. A better understanding of tumor-stromal interactions and the molecular alterations that result in stromal dysfunction may help to identify patients who will benefit from either more aggressive or risk-adapted therapy regimens, and/or novel compounds that disrupt the tumor microenvironment and re-establishing normal control mechanisms.