Endometrial cancer is the most common gynecologic cancer in the United States and the fourth most common cancer in women. Although endometrial cancer most often presents at an early stage, when surgical treatment is effective, chemotherapy has become a critical component in the treatment of advanced or recurrent endometrial cancer. The use of chemotherapy has evolved and is now often administered to women with early-stage disease in the presence of high-risk features (eg, clear cell or serous histology), or in the adjuvant setting for women with advanced disease that has been surgically cytoreduced. There are no agents approved by the US Food and Drug Administration for second-line or later use in the setting of endometrial cancer. Options for women whose disease progresses after adjuvant chemotherapy have varying success. Therapies that target specific molecular pathways have emerged as promising treatments for endometrial cancer. Given the poor response rates for systemic chemotherapy in patients with advanced or recurrent disease, these novel agents have great potential to influence our care for women with endometrial cancer. In this article, we review the role of chemotherapy in the treatment of endometrial cancer, with an emphasis on first- and second-line treatment and novel agents in clinical trials.