The National Cancer Institute's Developmental Therapeutics Program (DTP) maintains the screening results obtained in 60 standardized cancer cell lines for ~43,000 compounds. Here the application of the categorical structure-activity relationship (cat-SAR) program for the identification of the structural attributes of identified compounds that display differential cytostatic or cytotoxic activity to one breast cancer cell line and not another is reported. The goal of this approach is to separate features associated with antiproliferative activity towards many cell lines from those that affect only a specific cell type. To assess this approach, SAR models were developed for cytostatic and cytotoxic activity against the human breast cancer cell lines MCF-7 and MDAMB-231 and three differential activity models for compounds that were potent cytostatic and cytotoxic agents in MCF-7 cells, but relatively inactive against MDA-MB-231 cells. The MCF-7 and MDA-MB-231 models comprised the most potent 200 active and least potent 200 inactive compounds found in the DTP database and the differential activity models comprised 200 compounds potent in one cell line and not the other and 200 compounds equally potent between the cell lines. Leave-one-out validations of the individual MCF-7 and MDA-MB-231 models returned values between 83 and 85% concordance, with values obtained between 66 and 76% concordance for the differential activity models. The cat-SAR approach identified the chemical attributes associated with cytostatic and cytotoxic activity for the MCF-7 and MDA-MB-231 breast cancer cell lines included in the DTP and furthermore, were able to differentiate the selective activity of compounds between the two breast cancer lines. Thus it is conceivable that such cell line-specific mechanisms could be exploited for the discovery of highly specific anti-breast cancer agents and could also potentially facilitate the development of SAR models with sufficient resolution and clarity to identify chemical moieties associated with antiproliferative activity towards selective individual cancer types while being innocuous to other cell types.