Breast cancers treated with the antiestrogen tamoxifen invariably become resistant. To analyze the behavior of cell subpopulations within a tumor following tamoxifen treatment, we have used a new flow cytometry-based immunoassay and software that simultaneously quantitate PR levels and the DNA indices of ploidy and cell cycle stage in total cell populations or any subset thereof. The human breast cancer cell line T47D and its clonal derivatives were used as models of stage IV breast cancer, and growth and PR were measured as markers of antiestrogen responsiveness. We demonstrate and quantitate a remarkable heterogeneity in PR content and show the existence of distinct subpopulations with large differences in their PR levels and DNA indices, even among T47D sublines that are clonally derived. Following chronic tamoxifen treatment, an overall decrease in PR levels and growth masks an extensive heterogeneity in the response of cell subpopulations. PR levels decrease in some cells but increase in others; populations having a growth advantage expand while others contract. We find little evidence that cells, unaffected by the hormone, gain a growth advantage. Rather than exhibiting autonomy, we propose that under the influence of tamoxifen, tumors become remodeled as selected subpopulations emerge that are stimulated by the hormone, explaining the paradoxical recurrence of disease in patients undergoing endocrine therapy.