The widespread use of progestin therapy for endometrial precancer/cancer introduces complexities in the interpretation of pathology specimens. This chapter delves into the nuanced morphological changes triggered by progestin therapy in both neoplastic and non-neoplastic endometrial tissues. Understanding these changes is crucial for accurate pathological diagnosis, thereby enabling clinicians to make strategic treatment decisions. The primary focus lies in discerning progestin-treated atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN), where the detection of residual or recurrent disease often involves significant interobserver variability and diagnostic challenges. Recent progress made in the utility biomarkers as adjuncts in the diagnosis of endometrial precancers, particularly in the context of post-progestin treated samples, is outlined. The utility of a PAX-2, PTEN, β-catenin immunohistochemistry panel, and the importance of uniform diagnostic reporting are discussed. The chapter amalgamates the existing literature, presents an effective diagnostic algorithm, and offers guidance for assessing endometrial biopsies in this setting. Lastly, it highlights recent insights into the molecular mechanisms that are thought to underlie the influences of progestins on normal and neoplastic endometrium, as well as in instances of progestin resistance.