This chapter discusses the regulatory role of endogenous mesenchymal stem cells (MSC) during an inflammatory response. MSC are a heterogeneous population of multipotent cells that normally contribute towards tissue maintenance and repair but have garnered significant scientific interest for their potent immunomodulatory potential. It is through these physicochemical interactions that MSC are able to exert an anti-inflammatory response on neighbouring stromal and haematopoietic cells. However, the impact of the chronic inflammatory environment on MSC function remains to be determined. Understanding the relationship of MSC between resolution of inflammation and autoimmunity will both offer new insights in the use of MSC as a therapeutic, and also their involvement in the pathogenesis of inflammatory disorders.