The lifetime risk for developing endometrial cancer, the fourth most common malignancy in women, is approximately 3%. Endometrial cancer is a hormone-driven cancer, with approximately 80% of endometrial cancers arising attributable to either an excess of estrogen or a lack of progesterone. In the normal endometrium, the proliferative effects of estrogen are normally countered by progesterone, but the absence of progesterone allows estrogen to induce oncogenesis, an effect that is amplified in situations of excess estrogen. One of the major emerging causes of the estrogen/progesterone imbalance is obesity. Obesity is associated with several hormonal derangements as well as dysregulation of insulin/insulin-like growth factor activity, which collectively contribute to hyperplasia and carcinogenesis in the endometrium. In this article, we provide an in-depth description of how obesity mechanistically promotes this hormone and growth factor imbalance. Given that endometrial cancer is clearly associated with obesity, we put forth the hypothesis that a large portion of these cancers might be prevented by treatment with progesterone.