The mesothelium consists of a single layer of flattened mesothelial cells that lines serosal cavities and the majority of internal organs, playing important roles in maintaining normal serosal integrity and function. A mesothelial ‘stem’ cell has not been identified, but evidence from numerous studies suggests that a progenitor mesothelial cell exists. Although mesothelial cells are of a mesodermal origin, they express characteristics of both epithelial and mesenchymal phenotypes. In addition, following injury, new mesothelium regenerates via centripetal ingrowth of cells from the wound edge and from a free-floating population of cells present in the serosal fluid, the origin of which is currently unknown. Recent findings have shown that mesothelial cells can undergo an epithelial to mesenchymal transition, and transform into myofibroblasts and possibly smooth muscle cells, suggesting plasticity in nature. Further evidence for a mesothelial progenitor comes from tissue engineering applications where mesothelial cells seeded onto tubular constructs have been used to generate vascular replacements and grafts to bridge transected nerve fibres. These findings suggest that mesothelial cell progenitors are able to switch between different cell phenotypes depending on the local environment. However, only by performing detailed investigations involving selective cell isolation, clonal analysis together with cell labelling and tracking studies, will we begin to determine the true existence of a mesothelial stem cell.