This review summarizes highlights of our experiments investigating mechanisms, mediators and sites by which endotoxin disrupts reproductive neuroendocrine activity and interferes with the estrous cycle of sheep. Endotoxin, or lipopolysaccharide (LPS), is a commonly used model for immune and inflammatory stress. When administered to ovary-intact ewes, endotoxin interrupts the follicular phase of the cycle by interfering with several steps in the preovulatory chain of endocrine events. One such step is the development of high frequency LH pulses, which provide an essential stimulus for the preovulatory increase in estradiol secretion from the ovarian follicle. Follow-up experiments in ovariectomized ewes demonstrate that endotoxin inhibits pulsatile LH secretion at both the hypothalamic and pituitary levels, suppressing pulsatile GnRH secretion and reducing pituitary responsiveness to GnRH. This disruption of GnRH and LH pulsatility is mediated by pathways that include the synthesis of prostaglandins and cortisol, both of which are increased by endotoxin. It is postulated that a prostaglandin-mediated pathway disrupts the cycle during immune and inflammatory stress, whereas a separate cortisol-mediated pathway reinforces this disruption and also participates more generally in suppressing cyclicity during other stressful situations that activate the hypothalamo-pituitary-adrenal axis.