Serosal tissues consist of a surface mesothelial layer and subsurface spindled connective tissue cells. Surface cells are decorated with antibodies to both low and high molecular weight cytokeratin whereas subserosal cells only express the intermediate filament vimentin. Serosal injury results in the proliferation of multipotential subserosal cells (MSC) which have the ultrastructural morphology of myofibroblasts and yet co-express low molecular weight cytokeratin and vimentin. These cells appear responsible for the re-establishment of surface mesothelium during which they acquire high molecular weight cytokeratin and loose vimentin. There are many parallels between reactive and neoplastic serosal tissues. Desmoplastic/sarcomatoid mesotheliomas resemble the MSC and co-express low molecular weight cytokeratin and vimentin and epithelial mesotheliomas resemble surface mesothelium and express both low and high molecular weight cytokeratin. The ability of normal serosal tissue to modulate its cell shape and intermediate filament expression helps understand the diversity of serosal tumors.