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Programmed Cell Death (PCD) is a highly regulated but not yet fully understood process by which selective gene expression leads to cell demise. The term apoptosis refers to the typical morphological changes observed with PCD. In the present study, we investigated the potential role of apoptosis as a mechanism by which anti-estrogens mediate tumor regression. Estrogen receptor-positive MCF-7 human mammary adenocarcinoma cells were treated with three different estrogen antagonists: RU 58668, ICI 182,780, and 4OH-Tam, in order of increasing potency. At selected time intervals, for up to seven days of culture, the degree of apoptosis induced by the anti-estrogens was assessed. Apoptotic cells were scored on the basis of specific morphological criteria disernable by fluorescence microscopy. It was hypothesised that the more potent the anti-estrogen, the greater the number of apoptotic cells we would observe. However, only minimal apoptosis was noted even at the highest concentration of anti-estrogen assayed (10-5 M). This is in contrast to some, but not all, previous reports. Possible confounding factors are discussed and include the presence of exogenous estrogen in the culture media, as well as a genetic drift in the clonal lineage of MCF-7 cells such that a resistance to induced apoptosis had been acquired.