The early discontinuation of the Women's Health Initiative trials of daily conjugated estrogens and medroxyprogesterone and of conjugated estrogens only was hailed as the "death to the use of hormone replacement regimens" in menopause. The analyses showed risks outweighing benefits of hormone therapy when given broadly to postmenopausal women. The expanding basic science and clinical research on the specific actions of sex steroids at the genomic and nongenomic level, however, shed new insight into these results. This review focuses on the vascular and metabolic effects of sex steroids to illustrate new advances. Understanding the mechanisms of sex steroid receptor action in a tissue-specific manner, ligand-specific dose responses, and the effects of steroid hormones in normal compared to diseased tissues may explain some of the outcomes in the clinical trials. Further research will clarify the potential benefits and risks of hormone therapy after menopause, both in individual patients and in selected populations.