Mesothelium is the simple squamous epithelium covering all abdominal organs and the coeloms in which those organs reside. While the structural characteristics of this cell type were documented a century ago, its potential in development, disease, and wound healing is only now becoming apparent. In the embryo, mesothelia provide vasculogenic cells for the developing heart, lungs, and gut. Furthermore, adult mesothelial cells can be reactivated using thymosin β4 and mobilized to aid in tissue repair. Despite their positive role in development and repair, mesothelia are also susceptible to adhesion and tumor formation. With knowledge that the mesothelium is an important mediator of tissue repair as well as disease, it will be important to identify other factors like thymosin β4 that have the ability to potentiate these cells. Future use of chemical and genetic agents in conjunction with mesothelial cells will lead to enhanced therapeutic potential and mitigation of deleterious outcomes.