Inhibitors of estrogen-related pathways have been used with some success in the treatment of breast cancer. These include the antiestrogens tamoxifen, more recently faslodex, and the aromatase inhibitor anastrazole. However, failure and recurrence rates are substantial with drugs countering the effects of estrogens. Progestins, unlike estrogens, have generally been considered to oppose breast cancer and have been used with reasonable efficacy after antiestrogen failure. However, a building body of evidence, from cell culture, animal studies, and, most recently, several major clinical studies involving hormone replacement therapy, strongly supports the notion that progestins generally stimulate breast cancer. Our studies and those of others suggest that progestins increase the numbers of breast cancer cells by both stimulating the rate of proliferation and inhibiting cell death. These data indicate that progestin-related pathways might provide effective targets for breast cancer therapy. This review addresses the rationale for using inhibitors of progestin-related pathways to treat breast cancer and comments on some possible points of attack.