Endometriosis is an estrogen-dependent inflammatory disease that develops in reproductive-aged women who experience pelvic pain and infertility. Even though endometriosis is not a new disease, its molecular etiology has not been clearly elucidated. Defects in the immune system might be one of the factors that promote endometriosis progression. For example, elevated levels of proinflammatory cytokines are associated with endometriosis. Interferon is one of the cytokines that is elevated in endometriotic tissues compared with normal endometrium. Therefore, high interferon levels play a crucial role in endometriosis progression. In addition to endometriosis, however, interferon has a critical role in endometrial function, particularly in the initiation and maintenance of pregnancy. Therefore, this review describes the double-edged sword of interferon signaling in normal endometrial function versus endometriosis progression and also discusses interferon targeting as a new nonhormonal therapy for endometriosis. This approach may increase the efficacy of endometriosis treatment and reduce the adverse effects associated with current hormonal therapy for this disease.