The termination of one of the trials in the Women's Health Initiative (WHI) study is causing turmoil in women using hormone therapy. Practitioners and patients alike are confronted with conflicting evidence about the safety and effectiveness of both estrogen therapy (ET) and hormone (estrogen/progestin) therapy (HT). Recent investigations of the estrogen receptor, the genome, and cellular cofactors have demonstrated the heterogeneity of molecular response to hormones. This implies a heterogeneous response in the individual as well and casts doubt on the validity of prior research. Recent experiments in monkeys have provided a possible explanation for the adverse effects of HT on the cardiovascular system that were detailed by the Heart and Estrogen/Progestin Replacement Study (HERS) and WHI studies. This article explores nuances of several key studies and discusses potential therapeutic options, including use of lower-dose estrogen, transdermal estrogen, selective estrogen-receptor modulators, and diminished use of progestin.