Evidence supports that a variety of cancers are sparked by the growth of cells that exhibit characteristics of stem cells. Such cancer-initiating cells are capable of populating a tumor with a heterogeneous group of daughter cells while still maintaining the ability to self-renew. Several groups have recently reported the identification of cancer-initiating cells in ovarian cancer, the most lethal gynecologic malignancy. Epithelial ovarian cancer comprises 90% of cancers of the ovary and consists of four major histologic types, each bearing some resemblance to tissues in the peritoneal cavity. Although epithelial ovarian cancer has traditionally been thought to originate from the single layer of cells surrounding each ovary, new findings suggest that many of these cancers derive from Müllerian epithelium. This raises questions about the origin of ovarian cancer-initiating cells, and if there may be more than one source. Despite the initial effectiveness of primary therapy against advanced stage ovarian cancer, most of these cases recur, months to years following diagnosis. The cause of disease recurrence is unknown, but may involve cancer-initiating cells that survive chemotherapy and enter a period of dormancy while residing in as-yet undefined niches within the body before being triggered to initiate renewed growth. Herein the nature of these cells is explored as well as novel approaches for therapeutic targeting.