Ovarian cancer is the most deadly gynaecological cancer with approximately 225,500 new cases diagnosed and 140,200 deaths yearly reported worldwide. While advances in surgery, chemotherapy, and radiation therapy over the past 20 years have led to improved outcomes, overall 5-year survival is only 40% for ovarian cancer compared with 90% for breast cancer and 63% for colorectal cancer. Various epidemiological and molecular studies have associated genetic and life style factors with the predisposition to developing ovarian cancer. Women with BRCA1/2 gene mutations have a genetic predisposition for developing ovarian cancer, but not all (~50%) of these women develop the disease. Epidemiological studies in large cohorts of women showed that breast-feeding, pregnancy/parity and combined oral contraceptive use significantly decreases, whereas, infertility and nulliparity increases their risk of developing ovarian cancer. Combined oral contraceptive use is the most effective preventive measure against ovarian cancer and approximately 50% reduction in ovarian cancer risk occurs after 3-5 years of use. How ovarian hormones regulate ovarian cancer development and progression is currently unclear. Using human fallopian tube tissue samples and mouse models, we have dissected underlying molecular mechanisms of hormonal control of ovarian cancer. Our findings provide evidence that progesterone suppresses the growth of ovarian cancer initiating lesions and thereby provides protection against developing ovarian cancer.