Patients with endometrial cancer have an overall good prognosis. Patients with tumors invading deep into the myometrium or the cervical stroma or with extrauterine spread and patients with uterine papillary serous carcinoma (UPSC) or clear cell carcinoma (CCC) are at increased risk of relapse and represent a therapeutic challenge. Surgical treatment remains the cornerstone of therapy. Hysterectomy with bilateral salpingo-oophorectomy, washings, and careful assessment for intra-abdominal tumor should be performed with pelvic and para-aortic lymph node dissection when indicated based on grade of tumor and depth of invasion. All patients with UPSC or CCC should have pelvic and para-aortic lymph node dissection and omentectomy performed. Gross extrauterine disease should be resected. Radiotherapy has been the traditional adjuvant treatment for all high-risk patients. For patients with advanced disease (stage III-IV) combination chemotherapy with cisplatin and doxorubicin has been found to be superior to radiotherapy. For patients with advanced disease, treatment with a three-drug combination of cisplatin, doxorubicin, and paclitaxel has been shown to increase survival. It remains to be seen whether adjuvant chemotherapy in patients with high-risk disease in a lower stage will improve survival and possibly replace adjuvant radiotherapy in some patient groups.