Differentiation of intestinal epithelial cells involves a complex process of establishment of cell polarity, commitment to cell lineage, and inhibition of cell division. Polarized epithelial cells are characterized by specific junctional complexes and cytoskeletal proteins which produce specific membrane domains. Intestinal cytoskeletal proteins are often preserved in neoplastic colonic tissues, and can be used to identify the cell of origin of poorly differentiated cancers. In this context, these proteins are markersof organ-specificdifferentiation. In addition, since loss of cytoskeletal polarity commonly occurs in transformedcells, aberrant expression of these proteins may be used as a rnarkerof neoplasia in the colon. Normal polarization of basolateral proteins (secretory component) and apical proteins such as brush border hydrolases, cytoskeletal proteins (villin, fodrin), and carcinoembryonic antigen can become disrupted in adenomas and cancers. Cytoskeletal intermediate filaments (cyiokeratins) demonstrate increased immunoreactivity in villous adenomas and cancers compared with normal colonic crypts. Altered actin bundles are found in preneoplastic mucosa such as colon from patients with familial polyposis coli. Molecular mechanisms responsible for altered cytoskeletal structures remain unclear; however, altered protein phosphorylation most likely plays a role. For example, the phosphorylation status of cytoskeletal and junctional complex proteins appears to influence their solubility and interactive properties, which may result in altered cell polarity. Markers of altered cytoskeletal structure and polarity can identify neoplastic colonocytes; however, the extent to which they can be used as intermediate markers of colonic neoplasia remains to be determined.