Areas covered: This article reviews how key interactions between tumor epithelial cells and surrounding mesenchymal and immune cells can promote tumor progression and highlights molecular elements that might represent novel therapeutic targets. Expert opinion: The tumor microenvironment is increasingly being viewed as a potential therapeutic target with a number of strategies being developed to disrupt tumor--stroma interactions, in order to delay or circumvent tumor progression. Targeting elements of the tumor microenvironment, or signaling pathways in tumor cells activated as a consequence of stromal interactions, may prove a useful therapeutic strategy to prevent tumor development and progression. However, given the tumor cells' ability to circumvent various therapeutic agents when given as monotherapy, the success of these agents is likely to be seen when used in combination with existing treatments.