Progesterone therapy is an effective treatment for atypical endometrial hyperplasia and early endometrial carcinoma (EC). However, progesterone resistance is the main obstacle to the success of conservative treatment in women with type I EC and remains a major clinical challenge. Studies indicate that progesterone and progesterone receptors (PRs) play a significant role in both normal and neoplastic endometria. Most EC arises in the epithelial cells of the endometrial glands, and a large body of in vitro evidence suggests that the absence or reduced expression of PR isoform B might result in the failure of progesterone treatment and lead to aberrant PRB-mediated signalling in EC cells. A recently developed in vivo knockout mouse model suggests that enhanced DNA methylation decreases the level of stromal PR isoform A and that this is also a main contributor to progesterone resistance in EC cells. The endometrial stroma within the EC might create a microenvironment that determines how epithelial-derived cancer cells respond to progesterone. This novel study opened a new avenue for research seeking to clarify the mechanisms that regulate the specific PR isoforms that are associated with the stromal cell responses to progesterone and has led to new understanding of both endometrial cell-specific and mechanical contributions of the stroma to EC development.