Endometrial cancer is the sixth leading cause of cancer-related death in women worldwide. Many endometrial cancers occur in young women who have a desire to maintain their fertility. Therefore, conservative medical treatment with progestin is quite common in this patient group. However, approximately 30% of these patients progress although the resistance mechanisms have been unclear. In this article, Dr. Zheng’s group have identified a novel molecular mechanism of progestin resistance that may have therapeutic applications in clinic.