Advanced and metastatic endometrial cancer (EC) is associated with a poor prognosis despite the avaibility of systemic treatments including endocrine therapy and combination cytotoxic chemotherapy. Response rates of systemic treatments are associated with high toxity, have poor response rates and responses generally are short lasting. Recent findings on the molecular aberrations of the subtypes of EC have enabled in vitro and in vivo studies to exploit targeted treatment for this disease. One of the most common molecular aberrations in EC is the P13K-AKT-mTOR pathway being activated through different mechanisms in both, type I and type II ECs. The aim of this review is to summarize the numerous preclinical and clinical studies and discuss the future directions.