The utilization of mesenchymal stem cells (also known as mesenchymal stromal cells (MSCs)) as a cell-based therapy for diseases that have ongoing inflammatory damage has become increasingly available. Our understanding of the cell biology of MSCs is still incomplete. However, as a result of increasing numbers of preclinical and clinical studies, general themes are emerging. The capacity of MSCs to reduce disease burden is largely associated with their ability to modulate the activity of the host immune responses rather than to contribute directly to tissue regeneration. As a result, they have significant potential in the treatment of chronic inflammatory disease regardless of the affected tissue. For example, MSC-based therapies have been developed in the context of diseases as diverse as rheumatoid arthritis and multiple sclerosis. Here, we discuss some of the principles that link these conditions and the aspects of MSC biology that contribute to their use as a therapy for chronic inflammatory conditions.