Progesterone is a steroid hormone that is essential for the regulation of reproductive function. The main physiological roles of this hormone have been widely described. Progesterone and progestins have been approved for a number of indications including the treatment of irregular and anovulatory menstrual cycles and, when combined with estrogen, for contraception, and the prevention of endometrial hyperplasia in postmenopausal hormonal replacement therapy (HRT) regimens. Lack of understanding between the differences in categories of the progestins as well as with the physiological hormone has resulted in considerable controversy surrounding the use of progestins for HRT regimens. Newer evidence suggests that there are distinct differences between the molecules and there is no progestin class effect, with regard to benefits or side-effects. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system and the vessels. Recently, it has been shown in animal experiments that progesterone and the progestin Nestorone® have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. The potential benefits of natural progesterone and its related derivatives warrant further investigation. It is hoped that a better understanding of the mechanism of action of progesterone and selected progestins will help in defining better therapies for men and women.