The effect of progestins on proliferation of breast cancer has been a controversial area. We have consistently reported progestin stimulation of proliferation in the progesterone receptor-rich human breast cancer cell line T47D. Other authors, under other conditions, have agreed that progestins stimulate, but for just one turn of the cell cycle. To our knowledge, this is the first in vitro report to show progestin stimulation of human breast cancer cell growth for multiple, probably unlimited, cell cycles, while control cells are dying. This is accompanied by progestin up-regulation of the antiapoptotic protein bcl-xL, no effect on the pro-apoptotic protein bax, and, surprisingly, diminution of the antiapoptotic protein bcl-2. Thus, progestins both serve as survival factors and stimulate proliferation, implying a possible similar role in breast cancer patients. The data support the notion that many patients may benefit more from combined antiprogestin-antiestrogen therapy than from antiestrogen alone, and suggest bcl-x(L) as a possible target for breast cancer therapy.