Uterine papillary serous carcinoma (UPSC) is an extremely malignant tumor associated with a grim prognosis. It accounts for less than 10% of all cases of endometrial cancer. Mean age at presentation is 68 years. Morphological appearance is similar to poorly differentiated serous cancer of the ovary. A characteristic feature is extensive invasion of blood and lymph vessels and rapid intraperitoneal dissemination. Endometrial glandular dysplasia is currently considered a precursor lesion of UPSC. The basic pathogenetic event is mutation of suppressor gene TP53 and overexpression of HER2/neu (human epithelial growth factor receptor 2). UPSC differs morphologically, genetically and clinically from endometrioid cancer. It is usually diagnosed in slender elderly women and is not correlated with hormonal risk factors. The serous type, in contrast to endometrioid cancer (EEC) usually developing within atypical proliferative lesion, develops mainly within atrophic endometrium, is characterized by high grade of malignancy (G3) and aggressive clinical course. Metastases within the abdominal cavity and lymph nodes develop rapidly and recurrences are usually distant and multifocal. Every case of endometrial cancer of any grade, with a component of serous cancer, should be treated like serous cancer of the ovary. Properly performed staging includes: hysterectomy with adnexectomy, pelvic and periaortal lymphadenectomy, omentectomy and inspection of the peritoneal cavity, as in the case of ovarian cancer. Adjuvant treatment includes chemotherapy based on platinum and taxane with or without radiotherapy. High frequency of extrauterine serous foci even at early stages of the disease necessitates an aggressive and multimodal therapeutic approach. Unfavorable treatment outcomes in UPSC reported to date, force us to search for novel therapeutic techniques, based mainly on targeted therapies.