The utility and safety of postmenopausal hormone replacement therapy (HRT) has recently been put into question by large clinical trials. Their outcome has been extensively commented upon, but discussions have mainly been limited to the effects of estrogens. In fact, progestagens are generally only considered with respect to their usefulness in preventing estrogen stimulation of uterine hyperplasia and malignancy. In addition, various risks have been attributed to progestagens, and their omission from HRT has been considered, but this may be to underestimate their potential benefits and therapeutic promises. A major reason for the controversial reputation of progestagens is that they are generally considered as a single class. Moreover, the term progesterone is often used as a generic one for the different types of both natural and synthetic progestagens. This is not appropriate, as natural progesterone has properties very distinct from the synthetic progestins. Within the nervous system, the neuroprotective and promyelinating effects of progesterone are promising not only for preventing, but also for reversing, age-dependent changes and dysfunctions. There is indeed strong evidence that the aging nervous system remains at least to some extent sensitive to these beneficial effects of progesterone. The actions of progesterone in peripheral target tissues including breast, blood vessels and bones are less well understood, but there is evidence for its beneficial effects. The variety of signaling mechanisms of progesterone offers exciting possibilities for the development of more selective, efficient and safe progestagens. The recognition that progesterone is synthesized by neurons and glial cells requires a re-evaluation of hormonal aging.