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Tissue microarray (TMA) technology is currently being utilized as a complimentary histological tool for both normal target distribution and evaluation of pharmacodynamic biomarkers in support of the drug discovery process. The Automated Cellular Imaging System (ACIS-Clarient Chromavision) provides a rapid, precise approach to the quantitative analysis of immunohistochemically localised protein within TMAs. This system utilizes colour space analysis to determine the percentage of protein localization, in relation to a selected counterstained tissue component area, and relative optical intensity as an indication of protein density in TMAs. We describe the use of the ACIS under two situations (1) identification of novel target molecule distribution in normal animal TMAs and (2) analysis of a panel of immunohistochemical biomarkers to determine mode of action of novel anti-cancer drugs in xenograft TMAs. In the first case, the approach taken was to utilise a two-tiered analysis, identifying that protein expression was present in any particular tissue core and then reviewing those cores for the specific cellular distribution of protein. In the second example, immunohistochemistry on TMA samples was used to determine the pharmacological effects of small molecule inhibitors on molecular targets and linked pathways, including apoptosis and endoreduplication. TMAs were also stained by the histochemical Blue Feulgen method for ploidy evaluation on the ACIS. These analyses have indicated the value of using a combination of Chromavision ACIS and histological analysis of TMAs for both novel target distributions in drug discovery and in predicting the efficacy of cyclin and mitosis inhibitors in preclinical models.