Endometrial cancer is the most common gynecologic malignancy and represents a major health concern because overall five-year survival rates have not improved in the last three decades. A great deal of research demonstrates that the endometrium is extremely sensitive to hormones, and a shift in the estrogen:progesterone balance is the major cause for the development of endometrial cancer. Progestin-based therapy has proven effective in a subset of patients, particularly in situations where expression of progesterone receptor (PR) is maintained. However, this approach is not routinely used in the clinic in the U.S. for several reasons. For example, many endometrial tumors have lost PR expression, which limits the clinical application of progestin-based therapy. While the idea that restoring PR expression will resensitize tumors to progestin was proposed over 20 years ago, we only now have the molecular tools to accomplish this goal. Basic science research has revealed several pathways that govern the expression of PR at the DNA, RNA, and protein levels. In this article, we describe one current approach to restore expression of PR at the epigenetic level in endometrial cancer. While still in the preclinical stage, we believe this strategy to re-establish PR expression will result in resensitization of endometrial tumors to progestin therapy.