Selective estrogen receptor modulators (SERMs) mimic estrogen action in certain tissues while opposing it in others. The therapeutic effectiveness of SERMs such as tamoxifen and raloxifene in breast cancer depends on their antiestrogenic activity. In the uterus, however, tamoxifen is estrogenic. Here, we show that both tamoxifen and raloxifene induce the recruitment of corepressors to target gene promoters in mammary cells. In endometrial cells, tamoxifen, but not raloxifene, acts like estrogen by stimulating the recruitment of coactivators to a subset of genes. The estrogen-like activity of tamoxifen in the uterus requires a high level of steroid receptor coactivator 1 (SRC-1) expression. Thus cell type– and promoter-specific differences in coregulator recruitment determine the cellular response to SERMs.