As many as 5% of women may experience menopause at or before age 45 (POF). Four causes are known for POF: (1) Genetic. Clear-cut X chromosome deletions, particularly those in the critical region, result in truncation of reproductive lifespan. Creation of a central genetic data bank for women with POF may assist in defining the genetic contribution to this condition. (2) Autoimmune. POF coexists with virtually all of the permutations of the autoimmune polyglandular failure syndromes, most often in linkage with antithyroid and antiadrenal antibodies. (3) Iatrogenic. Iatrogenic POF results from repeated ovarian surgeries, or from the underlying disease that led to the surgery. (4) Environmental. Environmental toxicants are difficult to pinpoint, but evidence suggests that galactose consumption is linked to early menopause. We investigated the possibility that POF represented premature endocrine aging that was generalized, rather than specifically targeted to the ovary. Detailed investigation of the gonadotropin-releasing hormone-luteinizing hormone system, the somatotrophic axis, the adrenal glucocorticoid and androgen axes, and the prolactin axis have led us to conclude that women with POF are not prematurely aged in any endocrine system other than the ovary. Basic research on how the ovary interacts with the immune system, particularly in the early stages of oogenesis, how the oocyte and follicle interact in fetal life, and how follicles might be protected from damage in the case of immune self-attack are all fruitful avenues of clinically applicable work that may lead to treatments for this most vexing reproductive disorder.