The Chemoprevention Branch, NCI, is supporting over 80 clinical trials of chemopreventive agents and has dozens of drugs under development. The structural and functional properties of epithelial precancer (also called preinvasive or IEN), such as increasingly aberrant nuclear size, shape and rates of cellular proliferation and apoptosis, measured by CAQIA, form the basis for specific and quantitative end markers in short term clinical trials of chemopreventive agents. IEN very frequently, if not invariably, is preceded by two conditions diffusely affecting the epithelium: genomic instability and chronic hyperplasia. Chronic subepithelial inflammation is also commonly present. Multicentricity and multipath genetic progression of individual lesions are important characteristics that must be considered when designing endpoint markers and planning for adequate biopsy sampling in clinical trials of chemopreventive agents. Use of CAQIA provides increased sensitivity and specificity when measuring the cellular changes of IEN, such as increasingly aberrant nuclear size, nuclear shape, integrated optical density of nuclear DNA and nuclear chromatin texture features. A software program called the Deep Valley Detector, which measures the optical density gradient at the margins of chromatin clumps in cell nuclei of histological sections stained for DNA, is one example of many nuclear chromatin texture features measured. In the image of the nucleus of a neoplastic cell from high grade IEN of the cervix, 111 deep valley sites were counted, whereas the nucleus of a non-neoplastic hyperplastic cell showed only 16 sites. The modulating effects of chemopreventive agents on IEN may be quantitated by the change they produce in the average number of deep valley sites per nucleus.