The tumour microenvironment plays important roles in cancer initiation, growth, progression, invasion and metastasis, yet the molecular basis underlying these tumour-promoting effects is not fully delineated. Recent advances in gene expression, genetic and epigenetic profiling of stromal cells have improved our understanding of how mesenchymal-epithelial cell interactions may create a permissive microenvironment for malignancy and identified potential targets for cancer prevention and treatment including chemokine and cytokine networks. However, translating these findings into clinical practice may be difficult due to the complexity and redundancy of the interactions and the inherent ability of tumour epithelial cells to evolve and thrive in diverse environmental conditions.