In addition to the estrogen receptor, the progesterone receptor plays an important role in the growth of uterine fibroids. Several selective progesterone receptor modulators (SPRMs) have been evaluated for medical treatment of uterine fibroids and, because of safety issues, some molecules were stopped during clinical development. However, in 2012, ulipristal acetate received the approval for a pre-surgical treatment of uterine fibroids. Clinical trials with ulipristal acetate for long-term medical treatment of uterine fibroids are ongoing. This review article describes the action of SPRMs at the progesterone receptor level and the mechanism of action on the fibroid tissue. A review of the published clinical trials is performed, including the current evidence of efficacy on uterine fibroid symptom management, size reduction and tolerability. The therapeutic potential of SPRMs for uterine fibroids is discussed.