Reverse genetics is one strategy that is currently used to establish a link between a target gene and a disease phenotype. In this process, the function of a gene is inhibited and the consequence of its loss on a desired biological function, such as tumor growth and metastasis, is monitored. RNA interference (RNAi) has been found to be the most effective method to specifically inhibit gene expression. Notably, interactions between cancer cells, stromal cells, and the extracellular matrix (ECM) are crucial to angiogenesis and tumorigenesis. Tumor cells and the surrounding stroma are the principle source of growth factors and cytokines, which induce remodeling of the ECM mediated by metalloproteases (MMPs) secreted by macrophages. The production of macrophages is regulated by colony-stimulating factor (CSF)-1, which is overexpressed in several tumors. When short-interfering RNAs (siRNAs) targeting either the CSF-1 or its receptors were delivered into colon and breast cancer xenografts in mice, tumor growth was inhibited. Associated with this suppression, we observed decreased tumor vascularity, reduced expression of angiogenic factors and MMPs, and decreased macrophage recruitment to the tumors. The suppression of CSF-1 by RNA interference is therefore a powerful tool to block gene function and influence tumor-stroma interactions in solid tumor development.