Endometriosis is a painful gynecological condition in the fertile-age in which presence of endometrial tissue develops outside the uterus, which under normal situation found only in the inside lining of the uterus, attach to pelvic floor, endometrium or peritoneal cavity. Endometriosis cause abdominal pain, bleeding, irregular menstrual cycles with excessive pain, inflammatory responses and infertility. Retrogressive menstruation and invasion theories have been well studied in the pathogenesis of endometriosis. Role of steroids including estrogen, gonadotropin releasing hormones has been documented and major treatment strategies are based on steroid biology of endometriosis. Current treatment strategies are less successful and solely focusing on the late phase of the disease. The exact role of progesterone in the initiation (initial phase) of endometriosis has not been well studied or overshadowed by the concept of progesterone resistance that occurs in late phase in endometriosis. In this review, we are discussing the role of progesterone and potential use of anitprogestins or possible combination treatment strategies which may help to combat initiation and progression of endometriosis.