Chronic inflammation plays a significant enabling role in the tumorigenic process mediated mainly through the local production of cytokines, chemokines, growth factors, reactive oxygen species and nitrogen intermediates (ROS and RNI) by immune cells, which may lead to hyper-proliferation, resistance to apoptosis of pre-malignant cells, epithelial barrier permeability, epigenetic alterations, inactivation of DNA repair mechanism and modulation of anti-tumor immune responses. We will discuss, recent data revealing that besides immune cells, mesenchymal cells can also function as innate immune modulators and play dominant roles in the initiation, progression and metastasis of tumor. Upon injury, inflammation or neoplastic transformation, mesenchymal cells respond to innate stimuli from the microenvironment – mainly cytokines and chemokines (TGFβ, CXCL12 and interleukins) - that can lead to their recruitment and activation. A growing list of mediators released by activated MCs and CAFs, including chemokines, cytokines and proinvasive matrix-degrading enzymes then serve as effectors of their tumor-promoting or antagonizing actions. These immuno-modulatory roles of mesenchymal cells offer exciting new links between inflammation, immunity and cancer and could prove essential for the discovery of novel mechanisms in cancer pathogenesis, stratification and treatment.