The development of a baboon model of induced endometriosis, which recapitulates the retrograde menstruation hypothesis, has greatly facilitated our understanding of the early events associated with the disease process. Sequential analysis of the eutopic endometrium following the establishment of disease suggests that the development of progesterone resistance is a gradual process and becomes evident after 6 months of disease induction. This resistance is manifested by a decreased responsiveness of the progesterone receptor and its chaperone immunophilins as well as epigenetic modifications of progesterone-regulated genes. In comparative studies, the time-dependent changes observed in the baboon eutopic endometrium are similar to those that have been reported to be altered in women with endometriosis. The baboon model therefore provides insight into the potential mechanisms by which genes in the eutopic endometrium are dysregulated and how this alteration results in infertility that is associated with endometriosis.