Uterine papillary serous carcinoma (UPSC) affects 1% to 10% of patients with endometrial malignancies. UPSC is more aggressive than conventional endometrial cancer because UPSC presents with advanced disease, similar to epithelial ovarian cancer. There are several biomarkers for UPSC, which indicate that the pathogenesis of this condition is different than epithelial ovarian and conventional endometrial cancer. There are no risk factors for UPSC. Extended surgical staging is the optimal surgical approach for patients without known distant metastases. Patients with stage IA disease do not benefit from further adjuvant therapy. Adjuvant pelvic radiotherapy reduces pelvic relapse in intermediate- and high-risk patients (stage IC, II, and III disease) and extends survival rates of patients when administered with chemotherapy. In this setting, chemotherapy (with or without adjuvant radiotherapy) is a platinum-based regimen, combined with doxorubicin and cyclophosphamide. A newer regimen is paclitaxel, with or without platinum. An alternative approach for treating patients with UPSC has been to use whole abdominal radiotherapy. The results of Gynecologic Oncology Group protocol 122, which involves patients with UPSC who are being treated with chemotherapy and whole abdominal radiotherapy, are expected to reveal a minimal difference between these arms in overall survival rates. In patients experiencing distant or extensive abdominal relapse, management has been palliative, using platinum-based regimens or single-agent therapy to assess response. Treatment for patients with further relapse must be individualized because there are no studies addressing these scenarios. Palliative radiotherapy should be offered to patients needing symptom control for metastatic or progressive local disease. Many of these patients face a significant risk of treatment failure and death because of distant relapse. Therefore, the use of randomized trials to evaluate new therapies is critical.