Since the publication of the Women's Health Initiative (WHI) study followed by the results of the Million Women Study (MWS), the role of hormonal therapy in postmenopausal women has been further challenged. The risks attributed to hormone therapy have been overestimated and the data has been wrongly extrapolated to the whole class of therapies. The trends in postmenopausal hormonal therapy seem now to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus, based on the assumption that a lesser stimulation of the liver proteins and a neutral metabolic profile would be more favorable in terms of cardiovascular and venous risk. The combination of non-oral administration of estradiol and local delivery of progesterone or a progestin such as levonorgestrel by means of gels, sprays, vaginal rings or intrauterine systems would represent new methods of replacement therapy for the menopausal woman, improving compliance and minimizing the risks of hormone replacement. Several of these systems are either available or in development. Long-term studies on the risk/benefit of various non-oral formulations are certainly warranted.