One of the most prevalent potential therapeutic targets for women with endometrioid endometrial cancer (EC) is the estrogen receptor (ER)/progesterone receptor (PR) pathway. Despite a high proportion of endometrioid ECs being ER and/or PR positive, endocrine therapy is only effective in a minority of women with EC and ultimately patients progress with resistance developing to treatment. A variety of treatment approaches with progestins, selective ER modulators (SERMs) and aromatase inhibitors (AIs) are available. Exploration of these agents is desirable given their favorable toxicity profile. Greater understanding of ER and PR biology may help identify patient populations who will derive benefit and strategies for new therapeutic options. Here we review the clinical efficacy of endocrine therapy in EC, discuss the role of ER and/or PR as prognostic biomarkers, describe disease-specific mechanisms of resistance to endocrine therapy and explore potential strategies to enhance response for the “next generation” of endocrine therapy clinical trials. We also describe the use of endocrine therapy in younger women seeking to pursue fertility sparing options for management of EC. •A high proportion of endometrioid endometrial cancers are estrogen receptor (ER) and/or progesterone receptor (PR) positive.•Responses of endometrial cancers to single-agent progestins, selective ER modulators and aromatase inhibitors are low.•Understanding mechanisms of resistance to endocrine therapy has generated opportunities to enhance responses to treatment.•Clinical trials evaluating novel combination therapies are highly desirable to optimize ER/PR targeted treatment approaches.