The pathogenesis of high-grade serous carcinoma of the ovary has come into sharper focus as closer attention has been paid to the earlier phases of this disease. The study of patients with BRCA mutation has been of particular value, in as much as the examination of prophylactic salpingo-oophorectomies will reveal an early cancer in approximately 5% of individuals. Recently studies have shown that about 80% of these early carcinomas originate in the distal fallopian tube. This review summarizes the recent data supporting the distal fallopian tube as an important site for serous carcinogenesis, stressing both the presence of a novel precursor (the p53 signature) and the application of this model to all women irrespective of BRCA status. The challenges and unmet needs unmasked by this paradigm shift in ovarian cancer research are discussed.