The overall survival rate of patients with early-stage endometrial cancer is relatively high; however, there are few treatment options for patients with advanced or recurrent endometrial cancer, and the prognosis of such patients remains poor. Recent progress in molecular-targeted therapies demonstrated that they have the potential to improve the long-term survival of cancer patients with appropriate biomarkers. However, the median progression-free survival of patients who received single-agent molecular-targeted therapy was <5 months, and the development of molecular-targeted therapies for endometrial cancer patients is urgently needed. This review highlights the previous efforts, including antiangiogenesis therapy, PI3K/AKT/mTOR pathway inhibitor treatment and epidermal growth factor receptor inhibitor treatment and reports on ongoing phase 2 clinical trials, including immune checkpoint inhibitor and PARP inhibitor. We also summarized the genetic background of endometrial cancer according to The Cancer Genome Atlas data and considered the theoretical background for future efforts to prolong the survival of patients with refractory endometrial cancer and for other interesting challenges.