Uterine serous carcinoma and uterine carcinosarcoma are among the rarest but most lethal endometrial cancer sub-types, accounting for 15% of all cases, and are responsible for more than 50% of related deaths. These malignancies are distinguished by a high likelihood of metastasis and multisite recurrence, making them biologically different from other endometrial cancer sub-types. This review aims to analyze the existing evidence regarding molecular classification, new biomarkers, and innovative treatment approaches for these high-risk tumors. Herein, we explored the role of biomarkers, including HER2, TP53, and mismatch repair deficiency/microsatellite instability hypermutated and their influence on treatment strategies, surveillance approaches, the potential role of circulating tumor deoxyribonucleic acid, novel precision-based treatment options, and disparate survival outcomes for non-Hispanic Black and other underserved minority patients, along with strategies to improve outcomes for these patients. Substantial progress has been made in the last 5 years, prompting the following question: What lies ahead in the next 5 years? Our current understanding of uterine serous carcinoma and carcinosarcoma underscores the necessity of continuing to prioritize biomarker-driven therapies and the development of novel treatments through clinical trials while integrating these new strategies with traditional approaches, such as surgical resection and cytotoxic chemotherapy.