Achievements obtained in infertility treatments over the past two decades have sparked interest in optimizing progesterone administration. Although progesterone is absorbed orally when ingested in micronized form, bioavailability is poor because of extensive liver metabolism. This explains why full predecidual transformation of the endometrium cannot be achieved with oral progesterone and is therefore ineffective for luteal support in in vitro fertilization (IVF). Progesterone administered non-orally can duplicate the endometrial changes normally seen in the menstrual cycle in women whose ovaries are inactive. Similar results have been reported with intramuscular (i.m.) injections and vaginal administration, although tissue levels are higher in the latter case. The recent development of a controlled and sustained release vaginal progesterone gel, Crinone(R) 8%, has made the vaginal route clinically practical by limiting the number of necessary applications to 1 per day. This regimen has been found at least as effective as intramuscular (i.m.) injections in women whose ovaries are inactive (donor egg IVF) and for luteal support in regular IVF. Hence, painful daily i.m. injections of progesterone in oil become unnecessary. The possibility of reducing the number of daily applications of vaginal progesterone to 1 per day, made possible by the sustained release gel Crinone, has opened new possibilities for long-term treatments, as in hormone replacement therapy (HRT). The low incidence of systemic side effects with use of the vaginal progesterone gel used for HRT in amenorrheic women, contrasts with findings related to use of synthetic progestins. Preliminary data suggest that vaginal progesterone can be instrumental in enhancing the notoriously poor long-term compliance of HRT.